Compounds and uses thereof for the modulation of hemoglobin

ABSTRACT

Provide herein are compounds and pharmaceutical compositions suitable as modulators of hemoglobin, methods and intermediates for their preparation, and methods for their use in treating disorders mediated by hemoglobin and disorders that would benefit from tissue and/or cellular oxygenation.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No. 15/941,433, filed on Mar. 30, 2018, which is a continuation of U.S. application Ser. No. 14/776,603, filed on Sep. 14, 2015, now U.S. Pat. No. 9,981,939, which is the U.S. 371 National Stage application of International Application No. PCT/US2014/022789, filed on Mar. 10, 2014, which is a continuation-in-part of U.S. application Ser. No. 13/815,770, filed on Mar. 15, 2013, now U.S. Pat. No. 9,422,279, and which further claims priority to U.S. Provisional Application 61/905,802, filed on Nov. 18, 2013, and U.S. Provisional Application No. 61/905,803, filed on Nov. 18, 2013, the disclosures of each of the above referenced applications are incorporated herein by reference in their entireties and for all purposes.

FIELD OF THE INVENTION

This invention provides compounds and pharmaceutical compositions suitable as allosteric modulators of hemoglobin, methods and intermediates for their preparation, and methods for their use in treating disorders mediated by hemoglobin and disorders that would benefit from tissue and/or cellular oxygenation.

STATE OF THE ART

Sickle cell disease is a disorder of the red blood cells, found particularly among those of African and Mediterranean descent. The basis for sickle cell disease is found in sickle hemoglobin (HbS), which contains a point mutation relative to the prevalent peptide sequence of hemoglobin (Hb).

Hemoglobin (Hb) transports oxygen molecules from the lungs to various tissues and organs throughout the body. Hemoglobin binds and releases oxygen through conformational changes. Sickle hemoglobin (HbS) contains a point mutation where glutamic acid is replaced with valine, allowing HbS to become susceptible to polymerization to give the HbS containing red blood cells their characteristic sickle shape. The sickled cells are also more rigid than normal red blood cells, and their lack of flexibility can lead to blockage of blood vessels. U.S. Pat. No. 7,160,910 discloses compounds that are allosteric modulators of hemoglobin. However, a need exists for additional therapeutics that can treat disorders that are mediated by Hb or by abnormal Hb such as HbS.

SUMMARY OF THE INVENTION

This invention relates generally to compounds and pharmaceutical compositions suitable as allosteric modulators of hemoglobin. In some aspects, this invention relates to methods for treating disorders mediated by hemoglobin and disorders that would benefit from tissue and/or cellular oxygenation.

In certain aspects of the invention, a compound of formula (I) is provided:

-   -   or a tautomer thereof, or a pharmaceutically acceptable salt of         each thereof, wherein     -   L¹⁰ is optionally substituted methylene or, preferably, a bond;     -   is a single or a double bond;     -   each X and Y is independently (CR²⁰R²¹)_(e), O, S, SO, SO₂, or         NR²⁰; e is 1 to 4, preferably 1; each R²⁰ and R²¹ independently         is hydrogen or C₁-C₃ alkyl optionally substituted with 1-3 halo,         OH, or C₁-C₃ alkoxy, or CR²⁰R²¹ is C═O, provided that if one of         X and Y is O, S, SO, SO₂, then the other is not CO, and X and Y         are both not heteroatoms or oxidized forms thereof;     -   V¹ and V² independently are C₁-C₆ alkoxy; or V¹ and V² together         with the carbon atom they are attached to form a ring of         formula:

-   -   wherein each V³ and V⁴ are independently O, S, or NH, provided         that when one of V³ and V⁴ is S, the other is NH, and provided         that V³ and V⁴ are both not NH; q is 1 or 2; each V⁵ is         independently C₁-C₆ alkyl optionally substituted with 1-3 OH         groups, or V⁵ is CO₂R⁶⁰, where each R⁶⁰ independently is C₁-C₆         alkyl or hydrogen; t is 0, 1, 2, or 4; or CV¹V² is C═V, wherein         V is O, NOR⁸⁰, or NNR⁸¹R⁸²;     -   R⁸⁰ is optionally substituted C₁-C₆ alkyl;     -   R⁸¹ and R⁸² independently are selected from the group consisting         of hydrogen, optionally substituted C₁-C₆ alkyl, COR⁸³, or         CO₂R⁸⁴;     -   R⁸³ is hydrogen or optionally substituted C₁-C₆ alkyl; and     -   R⁸⁴ is optionally substituted C₁-C₆ alkyl;     -   provided that the compounds provided herein exclude those         disclosed in U.S. patent application Ser. Nos. 13/730,730 and         13/730,674; and     -   provided that the compounds provided herein exclude those in         Table 1 hereinbelow;     -   and A, B, and C are defined as follows.

In one instance,

-   -   ring A is C₆-C₁₀ aryl, or a 5-10 membered heteroaryl, wherein         the heteroatom is selected from the group consisting of O, N, S,         and oxidized forms of N and S, wherein each of the aryl, or         heteroaryl is optionally substituted, preferably with 1-4 C₁-C₆         alkyl and/or C₁-C₆ alkoxy groups;     -   ring B is:

-   -   wherein ring B′ including the —N—CO— moiety is a 5-6 membered         heterocycle containing up to 3 heteroatoms selected from         nitrogen, oxygen, and sulfur and oxidized forms of N and S,         wherein each of the heteroaryl and the heterocycle is optionally         substituted, preferably with 1-4 C₁-C₆ alkyl groups;     -   ring C is C₆-C₁₀ aryl or a 5-10 membered heteroaryl containing         up to 5 ring heteroatoms, wherein the heteroatom is selected         from the group consisting of O, N, S, and oxidized forms of N         and S, each of which is optionally substituted, preferably with         1-4: halo, oxo, —OR¹, C₁-C₆ alkyl, —COOR¹, and NR⁵R⁶,     -   R¹ is a hydrogen, C₁-C₆ alkyl or a prodrug moiety; wherein the         alkyl is optionally substituted with a 5-10 membered heteroaryl         containing up to 5 ring heteroatoms, wherein the heteroatom is         selected from the group consisting of O, N, S, and oxidized         forms of N and S, which is optionally substituted with with a         5-10 membered heteroaryl containing up to 5 ring heteroatoms,         wherein the heteroatom is selected from the group consisting of         O, N, S, and oxidized forms of N and S, wherein the heteroaryl         is optionally substituted with C₁-C₆ alkyl;     -   R⁵ and R⁶ are each independently hydrogen, optionally         substituted C₁-C₆ alkyl or —COOR³;     -   R³ is hydrogen or optionally substituted C₁-C₆ alkyl;     -   with the proviso that when ring C is C₆-C₁₀ aryl;     -   and ring B is optionally substituted 4-10 membered heterocyclyl;     -   then ring A excludes optionally substituted 5-10 membered         heteroaryl;     -   and provided that when ring C is C₆-C₁₀ aryl;     -   and ring B is optionally substituted 5-10 membered heteroaryl;     -   then ring A is not optionally substituted 4-10 membered         heterocycle.

In another instance:

-   -   ring A is C₆-C₁₀ aryl, a C₃-C₈ cycloalkyl, a 5-10 membered         heteroaryl or a 4-10 membered heterocycle containing up to 5         ring heteroatoms, wherein the heteroatom is selected from the         group consisting of O, N, S, and oxidized forms of N and S,         wherein each of the aryl, heteroaryl, cycloalkyl, or heterocycle         is optionally substituted, preferably with 1-4: halo, C₁-C₆         alkyl, C₁-C₆ alkoxy, and/or C₃-C₁₀ cycloalkyl, wherein the C₁-C₆         alkyl is optionally substituted with 1-5 halo, C₁-C₆ alkoxy,         and/or C₃-C₁₀ cycloalkyl;     -   ring B is a 5-10 membered heteroaryl or a 4-10 membered         heterocycle containing up to 5 ring heteroatoms, wherein the         heteroatom is selected from the group consisting of O, N, S, and         oxidized forms of N and S, wherein each of the heteroaryl and         the heterocycle is optionally substituted, preferably with 1-4:         halo, C₁-C₆ alkyl and/or —CO—C₁-C₆ alkyl,     -   is a single or a double bond;     -   ring C is C₆-C₁₀ aryl or a 5-10 membered heteroaryl containing         up to 5 ring heteroatoms, wherein the heteroatom is selected         from the group consisting of O, N, S, and oxidized forms of N         and S, each of which is optionally substituted, preferably with         1-4: halo, oxo, —OR¹, C₁-C₆ alkyl, —COOR¹, and/or C₁-C₆ alkoxy,         wherein the C₁-C₆ alkyl is optionally substituted with 1-5 halo,         C₁-C₆ alkoxy and/or a 4-10 membered heterocycle containing up to         5 ring heteroatoms, wherein the heteroatom is selected from the         group consisting of O, N, S, and oxidized forms of N and S; and     -   R¹ is hydrogen or a prodrug moiety;     -   provided that when ring C is C₆-C₁₀ aryl;     -   and ring B is optionally substituted 4-10 membered heterocyclyl;     -   then ring A excludes optionally substituted 5-10 membered         heteroaryl;     -   and provided that when ring C is C₆-C₁₀ aryl;     -   and ring B is optionally substituted 5-10 membered heteroaryl;     -   then ring A is not optionally substituted 4-10 membered         heterocycle.

In certain aspects of the invention, a compound of formula (X-I) is provided:

an N-oxide thereof, or a tautomer or each thereof, or a pharmaceutically acceptable salt of each of the preceding, wherein

-   -   ring A is phenyl optionally substituted with 1-3 halo and/or         C₁-C₆ alkoxy, or is a 4-10 membered heterocycle containing up to         3 ring heteroatoms, wherein the heteroatom is selected from the         group consisting of O, N, S, and oxidized forms of N and S,         optionally substituted, or is

-   -   -   wherein R⁷ is C₁-C₆ alkyl, optionally substituted with 3-3             fluoro groups, or is C₃-C₆ cycloalkyl;

    -   ring B is selected from the group consisting of

-   -   -   wherein R⁸ is C₁-C₆ alkyl, —CO—C₁-C₆ alkyl or a prodrug             moiety and wherein the pyridyl ring is optionally             substituted with a halo or an NR²⁵(CH₂)₂N(R²⁵)₂ group where             each R²⁵ is independently hydrogen or C₁-C₆ alkyl;

    -   X is O, S, SO, or SO₂;

    -   is a single or a double bond;

    -   ring C is phenyl or a 6 membered nitrogen-containing heteroaryl,         each of which is optionally substituted with 1-4: halo, oxo,         —OR¹, C₁-C₆ alkyl, —COOR¹ and/or C₁-C₆ alkoxy, wherein the C₁-C₆         alkyl is optionally substituted with 1-3 halo, C₁-C₆ alkoxy         and/or 4-10 membered heterocycle containing up to 3 ring         heteroatoms, wherein the heteroatom is selected from the group         consisting of O, N, S, and oxidized forms of N and S; and

    -   each R¹ is hydrogen or a prodrug moiety R;

    -   V¹ and V² independently are C₁-C₆ alkoxy; or V¹ and V² together         with the carbon atom they are attached to form a ring of         formula:

-   -   wherein each V³ and V⁴ are independently O, S, or NH, provided         that when one of V³ and V⁴ is S, the other is NH, and provided         that V³ and V⁴ are both not NH; q is 1 or 2; each V⁵ is         independently C₁-C₆ alkyl or CO₂R⁶⁰, where each R⁶⁰         independently is C₁-C₆ alkyl or hydrogen; t is 1, 2, or 4; or         CV¹V² is C=V, wherein V is O, NOR⁸⁰, or NNR⁸¹R⁸²;     -   wherein R⁸⁰ is optionally substituted C₁-C₆ alkyl;     -   R⁸¹ and R⁸² independently are selected from the group consisting         of hydrogen, optionally substituted C₁-C₆ alkyl, COR⁸³, or         CO₂R⁸⁴;     -   R⁸³ is hydrogen or optionally substituted C₁-C₆ alkyl;     -   R⁸⁴ is optionally substituted C₁-C₆ alkyl;     -   provided that when ring C is C₆-C₁₀ aryl;     -   and ring B is optionally substituted 4-10 membered heterocyclyl;     -   then ring A excludes optionally substituted 5-10 membered         heteroaryl; provided that when ring C is C₆-C₁₀ aryl;     -   and ring B is optionally substituted 5-10 membered heteroaryl;     -   then ring A is not optionally substituted 4-10 membered         heterocycle;     -   provided that the compounds provided herein exclude those         disclosed in U.S. patent application Ser. Nos. 13/730,730 and         13/730,674; and     -   provided that the compounds provided herein exclude those in         Table 1 hereinbelow.

Preferably, V¹ and V² together with the carbon atom they are attached to form a ring of formula:

In some embodiments, V¹ and V² independently are C₁-C₆ alkoxy; or V¹ and V² together with the carbon atom they are attached to form a ring of formula:

wherein each V³ and V⁴ are independently O, S, or NH, provided that when one or V³ and V⁴ is S the other is NH, and provided that V³ and V⁴ are both not NH; q is 1 or 2; each V⁵ is independently C₁-C₆ alkyl or CO₂R⁶⁰, where each R⁶⁰ independently is C₁-C₆ alkyl or hydrogen; t is 0, 1, 2, or 4; or CV¹V² is C=V, wherein V is O, and wherein the remaining variables are defined herein.

In certain embodiments, a compound of formula (II) is provided:

wherein the remaining variables are defined herein.

In certain embodiments, a compound selected from formulas (IIA), (IIB) and (IIC) is provided:

-   -   wherein     -   R⁹ is hydrogen, —OR¹, C₁-C₆ alkoxy optionally substituted with         1-3 C₁-C₆ alkoxy or 4-10 membered heterocycle containing up to 3         ring heteroatoms selected from N, O, S or oxidized forms         thereof;     -   R¹⁰ is hydrogen, hydroxy, halo or C₁-C₆ alkoxy;     -   R¹¹ is hydrogen or C₁-C₆ alkyl; and     -   R¹² is —OR¹;     -   wherein R¹ is hydrogen or the prodrug moiety R.

In certain aspects of the invention, a compound of formula (I) is provided:

-   -   or a tautomer thereof, or a pharmaceutically acceptable salt of         each thereof, wherein         -   L¹⁰ is optionally substituted methylene or, preferably, a             bond;         -   ring A is C₆-C₁₀ aryl, or a 3-10 membered heteroaryl,             wherein the heteroatom is selected from the group consisting             of O, N, S, and oxidized forms of N and S, wherein each of             the aryl, or heteroaryl is optionally substituted with 1-4             C₁-C₆ alkyl and/or C₁-C₆ alkoxy groups;         -   ring B is:

-   -   -   wherein ring B′ including the —N—CO— moiety is a 5-6             membered heterocycle containing up to 3 heteroatoms selected             from nitrogen, oxygen, and sulfur and oxidized forms of N             and S, wherein each of the heteroaryl and the heterocycle is             optionally substituted with 1-4 C₁-C₆ alkyl groups;         -   each X and Y is independently (CR²⁰R²¹)_(e), O, S, SO, SO₂,             or NR²⁰; e is 1 to 4, preferably 1; each R²⁰ and R²¹             independently is hydrogen or C₁-C₃ alkyl optionally             substituted with 1-3 halo, OH, or C₁-C₆ alkoxy, or CR²⁰R²¹             is C═O, provided that if one of X and Y is O, S, SO, SO₂,             then the other is not CO, and X and Y are both not             heteroatoms or oxidized forms thereof;         -   ring C is C₆-C₁₀ aryl or a 5-10 membered heteroaryl             containing up to 5 ring heteroatoms, wherein the heteroatom             is selected from the group consisting of O, N, S, and             oxidized forms of N and S, each of which is optionally             substituted with 1-4: halo, oxo, —OR¹, C₁-C₆ alkyl, —COOR⁵,             NR⁵R⁶,         -   R¹ is a hydrogen, C₁-C₆ alkyl or a prodrug moiety; wherein             the alkyl is optionally substituted with a 5-10 membered             heteroaryl containing up to 5 ring heteroatoms, wherein the             heteroatom is selected from the group consisting of O, N, S,             and oxidized forms of N and S, which is optionally             substituted with with a 5-10 membered heteroaryl containing             up to 5 ring heteroatoms, wherein the heteroatom is selected             from the group consisting of O, N, S, and oxidized forms of             N and S, wherein the heteroaryl is optionally substituted             with C₁-C₆ alkyl;         -   R⁵ and R⁶ are each independently hydrogen, optionally             substituted C₁-C₆ alkyl or —COOR³;         -   R³ is hydrogen or optionally substituted C₁-C₆ alkyl;         -   V¹ and V² independently are C₁-C₆ alkoxy; or V¹ and V²             together with the carbon atom they are attached to form a             ring of formula:

-   -   -   wherein each V³ and V⁴ are independently O, S, or NH,             provided that when one of V³ and V⁴ is S, the other is NH,             and provided that V³ and V⁴ are both not NH; q is 1 or 2;             each V⁵ is independently C₁-C₆ alkyl optionally substituted             with 1-3 OH groups, or V⁵ is CO₂R⁶⁰, where each R⁶⁰             independently is C₁-C₆ alkyl or hydrogen; t is 0, 1, 2, or             4; or CV¹V² is C=V, wherein V is O, NOR⁸⁰, or NNR⁸¹R⁸²;         -   R⁸⁰ is optionally substituted C₁-C₆ alkyl;         -   R⁸¹ and R⁸² independently are selected from the group             consisting of hydrogen, optionally substituted C₁-C₆ alkyl,             COR⁸³, or CO₂R⁸⁴;         -   R⁸³ is hydrogen or optionally substituted C₁-C₆ alkyl; and         -   R⁸⁴ is optionally substituted C₁-C₆ alkyl;         -   with the proviso that when ring C is C₆-C₁₀ aryl;         -   and ring B is optionally substituted 4-10 membered             heterocyclyl;         -   then ring A excludes optionally substituted 3-10 membered             heteroaryl;         -   and provided that when ring C is C₆-C₁₀ aryl;         -   and ring B is optionally substituted 3-10 membered             heteroaryl;         -   then ring A is not optionally substituted 4-10 membered             heterocycle.

In further aspects of the invention, a composition is provided comprising any of the compounds described herein, and at least a pharmaceutically acceptable excipient.

In still further aspects of the invention, a method is provided for increasing oxygen affinity of hemoglobin S in a subject, the method comprising administering to a subject in need thereof a therapeutically effective amount of any of the compounds or compositions described herein.

In further aspects of the invention, a method is provided for treating oxygen deficiency associated with sickle cell anemia, the method comprising administering to a subject in need thereof a therapeutically effective amount of any of the compounds or compositions described herein.

DETAILED DESCRIPTION OF THE INVENTION Definitions

It must be noted that as used herein and in the appended claims, the singular forms “a”, “an”, and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “a solvent” includes a plurality of such solvents.

As used herein, the term “comprising” or “comprises” is intended to mean that the compositions and methods include the recited elements, but not excluding others. “Consisting essentially of” when used to define compositions and methods, shall mean excluding other elements of any essential significance to the combination for the stated purpose. Thus, a composition or process consisting essentially of the elements as defined herein would not exclude other materials or steps that do not materially affect the basic and novel characteristic(s) of the claimed invention. “Consisting of” shall mean excluding more than trace elements of other ingredients and substantial method steps. Embodiments defined by each of these transition terms are within the scope of this invention.

Unless otherwise indicated, all numbers expressing quantities of ingredients, reaction conditions, and so forth used in the specification and claims are to be understood as being modified in all instances by the term “about.” Accordingly, unless indicated to the contrary, the numerical parameters set forth in the following specification and attached claims are approximations. Each numerical parameter should at least be construed in light of the number of reported significant digits and by applying ordinary rounding techniques. The term “about” when used before a numerical designation, e.g., temperature, time, amount, and concentration, including range, indicates approximations which may vary by (+) or (−) 10%, 5% or 1%.

As used herein, C_(m)-C_(n), such as C₁-C₁₂, C₁-C₈, or C₁-C₆ when used before a group refers to that group containing m to n carbon atoms.

The term “alkoxy” refers to —O-alkyl.

The term “alkyl” refers to monovalent saturated aliphatic hydrocarbyl groups having from 1 to 12 carbon atoms (i.e., C₁-C₁₂ alkyl) or 1 to 8 carbon atoms (i.e., C₁-C₈ alkyl), or 1 to 4 carbon atoms. This term includes, by way of example, linear and branched hydrocarbyl groups such as methyl (CH₃—), ethyl (CH₃CH₂—), n-propyl (CH₃CH₂CH₂—), isopropyl ((CH₃)₂CH—), n-butyl (CH₃CH₂CH₂CH₂—), isobutyl ((CH₃)₂CHCH₂—), rec-butyl ((CH₃)(CH₃CH₂)CH—), t-butyl ((CH₃)₃C—), n-pentyl (CH₃CH₂CH₂CH₂CH₂—), and neopentyl ((CH₃)₃CCH₂—).

The term “aryl” refers to a monovalent, aromatic mono- or bicyclic ring having 6-10 ring carbon atoms. Examples of aryl include phenyl and naphthyl. The condensed ring may or may not be aromatic provided that the point of attachment is at an aromatic carbon atom. For example, and without limitation, the following is an aryl group:

The term “—CO₂H ester” refers to an ester formed between the —CO₂H group and an alcohol, preferably an aliphatic alcohol. A preferred example included —CO₂R^(E), wherein R^(E) is alkyl or aryl group optionally substituted with an amino group.

The term “chiral moiety” refers to a moiety that is chiral. Such a moiety can possess one or more asymmetric centers. Preferably, the chiral moiety is enantiomerically enriched, and more preferably a single enantiomer. Non limiting examples of chiral moieties include chiral carboxylic acids, chiral amines, chiral amino acids, such as the naturally occurring amino acids, chiral alcohols including chiral steroids, and the likes.

The term “cycloalkyl” refers to a monovalent, preferably saturated, hydrocarbyl mono-, bi-, or tricyclic ring having 3-12 ring carbon atoms. While cycloalkyl, refers preferably to saturated hydrocarbyl rings, as used herein, it also includes rings containing 1-2 carbon-carbon double bonds. Nonlimiting examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamentyl, and the like. The condensed rings may or may not be non-aromatic hydrocarbyl rings provided that the point of attachment is at a cycloalkyl carbon atom. For example, and without limitation, the following is a cycloalkyl group;

The term “halo” refers to F, Cl, Br, and/or I.

The term “heteroaryl” refers to a monovalent, aromatic mono-, bi-, or tricyclic ring having 2-16 ring carbon atoms and 1-8 ring heteroatoms selected preferably from N, O, S, and P and oxidized forms of N, S, and P, provided that the ring contains at least 5 ring atoms. Nonlimiting examples of heteroaryl include furan, imidazole, oxadiazole, oxazole, pyridine, quinoline, and the like. The condensed rings may or may not be a heteroatom containing aromatic ring provided that the point of attachment is a heteroaryl atom. For example, and without limitation, the following is a heteroaryl group:

The term “heterocyclyl” or heterocycle refers to a non-aromatic, mono-, bi-, or tricyclic ring containing 2-12 ring carbon atoms and 1-8 ring heteroatoms selected preferably from N, O, S, and P and oxidized forms of N, S, and P, provided that the ring contains at least 3 ring atoms. While heterocyclyl preferably refers to saturated ring systems, it also includes ring systems containing 1-3 double bonds, provided that the ring is non-aromatic. Nonlimiting examples of heterocyclyl include, azalactones, oxazoline, piperidinyl, piperazinyl, pyrrolidinyl, tetrahydrofuranyl, and tetrahydropyranyl. The condensed rings may or may not contain a non-aromatic heteroatom containing ring provided that the point of attachment is a heterocyclyl group. For example, and without limitation, the following is a heterocyclyl group:

The term “hydrolyzing” refers to breaking an R^(H)—O—CO—, R^(H)—O—CS—, or an R^(H)—O—SO₂— moiety to an R^(H)—OH, preferably by adding water across the broken bond. A hydrolyzing is performed using various methods well known to the skilled artisan, non limiting examples of which include acidic and basic hydrolysis.

The term “oxo” refers to a C═O group, and to a substitution of 2 geminal hydrogen atoms with a C═O group.

The term “optionally substituted,” unless defined otherwise, refers to a substituted or unsubstituted group. The group may be substituted with one or more substituents, such as e.g., 1, 2, 3, 4 or 3 substituents. Preferably, the substituents are selected from the group consisting of oxo, halo, —CN, NO₂, —N₂+, —CO₂R¹⁰⁰, —OR¹⁰⁰, —SR¹⁰⁰, —SOR¹⁰⁰, —SO₂R¹⁰⁰, —NR¹⁰¹R¹⁰², —CONR¹⁰¹R¹⁰², —SC₂NR¹⁰¹R¹⁰², C₁-C₆ alkyl, C₁-C₆ alkoxy, —CR¹⁰⁰═C(R¹⁰⁰)₂, —CCR¹⁰⁰, C₃-C₁₀ cycloalkyl, C₃-C₁₀ heterocyclyl, C₆-C₁₂ aryl and C₂-C₁₂ heteroaryl, wherein each R¹⁰⁰ independently is hydrogen or C₁-C₈ alkyl; C₃-C₁₂ cycloalkyl; C₃-C₁₀ heterocyclyl; C₆-C₁₂ aryl; or C₂-C₁₂ heteroaryl; wherein each alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with 1-3 halo, 1-3 C₁-C₆ alkyl, 1-3 C₁-C₆ haloalkyl or 1-3 C₁-C₆ alkoxy groups. Preferably, the substituents are selected from the group consisting of chloro, fluoro, —OCH₃, methyl, ethyl, iso-propyl, cyclopropyl, vinyl, ethynyl, —CO₂H, —CO₂CH₃, —OCF₃, —CF₃ and —OCHF₂.

R¹⁰¹ and R¹⁰² independently is hydrogen; C₁-C₈ alkyl, optionally substituted with —CO₂H or an ester thereof, C₁-C₆ alkoxy, oxo, —CR¹⁰³═C(R¹⁰³)₂, —CCR, C₃-C₁₀ cycloalkyl, C₃-C₁₀ heterocyclyl, C₆-C₁₂ aryl, or C₂-C₁₂ heteroaryl, wherein each R¹⁰³ independently is hydrogen or C₁-C₈ alkyl; C₃-C₁₂ cycloalkyl; C₃-C₁₀ heterocyclyl; C₆-C₁₂ aryl; or C₂-C₁₂ heteroaryl; wherein each cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with 1-3 alkyl groups or 1-3 halo groups, or R¹⁰¹ and R¹⁰² together with the nitrogen atom they are attached to form a 3-7 membered heterocycle.

The term “pharmaceutically acceptable” refers to safe and non-toxic for in vivo, preferably, human administration.

The term “pharmaceutically acceptable salt” refers to a salt that is pharmaceutically acceptable.

The term “salt” refers to an ionic compound formed between an acid and a base. When the compound provided herein contains an acidic functionality, such salts include, without limitation, alkali metal, alkaline earth metal, and ammonium salts. As used herein, ammonium salts include, salts containing protonated nitrogen bases and alkylated nitrogen bases. Exemplary, and non-limiting cations useful in pharmaceutically acceptable salts include Na, K, Rb, Cs, NR₄, Ca, Ba, imidazolium, and ammonium cations based on naturally occurring amino acids. When the compounds utilized herein contain basic functionality, such salts include, without limitation, salts of organic acids, such as caroboxylic acids and sulfonic acids, and mineral acids, such as hydrogen halides, sulfuric acid, phosphoric acid, and the likes. Exemplary and non-limiting anions useful in pharmaceutically acceptable salts include oxalate, maleate, acetate, propionate, succinate, tartrate, chloride, sulfate, bisalfate, mono-, di-, and tribasic phosphate, mesylate, tosylate, and the likes.

The terms “treat”, “treating” or “treatment”, as used herein, include alleviating, abating or ameliorating a disease or condition or one or more symptoms thereof, preventing additional symptoms, ameliorating or preventing the underlying metabolic causes of symptoms, inhibiting the disease or condition, e.g., arresting or suppressing the development of the disease or condition, relieving the disease or condition, causing regression of the disease or condition, relieving a condition caused by the disease or condition, or suppressing the symptoms of the disease or condition, and are intended to include prophylaxis. The terms also include relieving the disease or conditions, e.g., causing the regression of clinical symptoms. The terms further include achieving a therapeutic benefit and/or a prophylactic benefit. By therapeutic benefit is meant eradication or amelioration of the underlying disorder being treated. Also, a therapeutic benefit is achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the individual, notwithstanding that the individual is still be afflicted with the underlying disorder. For prophylactic benefit, the compositions are administered to an individual at risk of developing a particular disease, or to an individual reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease has not been made.

The terms “preventing” or “prevention” refer to a reduction in risk of acquiring a disease or disorder (i.e., causing at least one of the clinical symptoms of the disease not to develop in a subject that may be exposed to or predisposed to the disease but does not yet experience or display symptoms of the disease). The terms further include causing the clinical symptoms not to develop, for example in a subject at risk of suffering from such a disease or disorder, thereby substantially averting onset of the disease or disorder.

The term “effective amount” refers to an amount that is effective for the treatment of a condition or disorder by an intranasal administration of a compound or composition described herein. In some embodiments, an effective amount of any of the compositions or dosage forms described herein is the amount used to treat a disorder mediated by hemoglobin or a disorder that would benefit from tissue and/or cellular oxygenation of any of the compositions or dosage forms described herein to a subject in need thereof.

The term “carrier” as used herein, refers to relatively nontoxic chemical compounds or agents that facilitate the incorporation of a compound into cells, e.g., red blood cells, or tissues.

As used herein, a “prodrug” is a compound that, after administration, is metabolized or otherwise converted to an active or more active form with respect to at least one property. To produce a prodrug, a pharmaceutically active compound can be modified chemically to render it less active or inactive, but the chemical modification is such that an active form of the compound is generated by metabolic or other biological processes. A prodrug may have, relative to the drug, altered metabolic stability or transport characteristics, fewer side effects or lower toxicity. For example, see the reference Nogrady, 1985, Medicinal Chemistry A Biochemical Approach, Oxford University Press, New York, pages 388-392. Prodrugs can also be prepared using compounds that are not drugs.

Compounds

In certain aspects of the invention, a compound of formula (I) is provided:

-   -   or a tautomer thereof, or a pharmaceutically acceptable salt of         each thereof, wherein L¹⁰ is optionally substituted methylene         or, preferably, a bond;     -   ring A is C₆-C₁₀ aryl, a C₃-C₈ cycloalkyl, a 5-10 membered         heteroaryl or a 4-10 membered heterocycle containing up to 5         ring heteroatoms, wherein the heteroatom is selected from the         group consisting of O, N, S, and oxidized forms of N and S,         wherein each of the aryl, heteroaryl, cycloalkyl, or heterocycle         is optionally substituted with 1-4: halo, C₁-C₆ alkyl, C₁-C₆         alkoxy, and/or C₃-C₁₀ cycloalkyl, wherein the C₁-C₆ alkyl is         optionally substituted with 1-5 halo, C₁-C₆ alkoxy, and/or         C₃-C₁₀ cycloalkyl; or     -   ring A is C₆-C₁₀ aryl, or a 5-10 membered heteroaryl, wherein         the heteroatom is selected from the group consisting of O, N, S,         and oxidized forms of N and S, wherein each of the aryl, or         heteroaryl is optionally substituted with 1-4 C₁-C₆ alkyl and/or         C₁-C₆ alkoxy groups;     -   ring B is a 5-10 membered heteroaryl or a 4-10 membered         heterocycle containing up to 5 ring heteroatoms, wherein the         heteroatom is selected from the group consisting of O, N, S, and         oxidized forms of N and S, wherein each of the heteroaryl and         the heterocycle is optionally substituted with 1-4: halo, C₁-C₆         alkyl and/or —CO—C₁-C₆ alkyl, or     -   ring B is:

-   -   wherein ring B′ including the —N—CO— moiety is a 5-6 membered         heterocycle containing up to 3 heteroatoms selected from         nitrogen, oxygen, and sulfur and oxidized forms of N and S,         wherein each of the heteroaryl and the heterocycle is optionally         substituted with 1-4 C₁-C₆ alkyl groups;     -   is a single or a double bond;     -   each X and Y is independently (CR²⁰R²¹)_(e), O, S, SO, SO₂, or         NR²⁰; e is 1 to 4, preferably 1; each R²⁰ and R²¹ independently         is hydrogen or C₁-C₃ alkyl optionally substituted with 1-3 halo,         OH, or C₁-C₆ alkoxy, or CR²⁰R²¹ is C═O, provided that if one of         X and Y is O, S, SO, SO₂, then the other is not CO, and X and Y         are both not heteroatoms or oxidized forms thereof;     -   ring C is C₆-C₁₀ aryl or a 5-10 membered heteroaryl containing         up to 5 ring heteroatoms, wherein the heteroatom is selected         from the group consisting of O, N, S, and oxidized forms of N         and S, each of which is optionally substituted with 1-4: halo,         oxo, —OR¹, C₁-C₆ alkyl, —COOR¹, and/or C₁-C₆ alkoxy, wherein the         C₁-C₆ alkyl is optionally substituted with 1-5 halo, C₁-C₆         alkoxy, and/or a 4-10 membered heterocycle containing up to 5         ring heteroatoms, wherein the heteroatom is selected from the         group consisting of O, N, S, and oxidized forms of N and S; or     -   ring C is C₆-C₁₀ aryl or a 5-10 membered heteroaryl containing         up to 5 ring heteroatoms, wherein the heteroatom is selected         from the group consisting of O, N, S, and oxidized forms of N         and S, each of which is optionally substituted with 1-4: halo,         oxo, —OR¹, C₁-C₆ alkyl, —COOR¹, NR⁵R⁶,     -   R¹ is a hydrogen, C₁-C₆ alkyl or a prodrug moiety; wherein the         alkyl is optionally substituted with a 5-10 membered heteroaryl         containing up to S ring heteroatoms, wherein the heteroatom is         selected from the group consisting of O, N, S, and oxidized         forms of N and S, which is optionally substituted with with a         5-10 membered heteroaryl containing up to S ring heteroatoms,         wherein the heteroatom is selected from the group consisting of         O, N, S, and oxidized forms of N and S, wherein the heteroaryl         is optionally substituted with C₁-C₆ alkyl;     -   R⁵ and R⁶ are each independently hydrogen, optionally         substituted C₁-C₆ alkyl or —COOR³;     -   R³ is hydrogen or optionally substituted C₁-C₆ alkyl;     -   V¹ and V² independently are C₁-C₆ alkoxy; or V¹ and V² together         with the carbon atom they are attached to form a ring of         formula:

-   -   wherein each V³ and V⁴ are independently O, S, or NH, provided         that when one of V³ and V⁴ is S, the other is NH, and provided         that V³ and V⁴ are both not NH; q is 1 or 2; each V⁵ is         independently C₁-C₆ alkyl optionally substituted with 1-3 OH         groups, or V⁵ is CO₂R⁶⁰, where each R⁶⁰ independently is C₁-C₆         alkyl or hydrogen; t is 0, 1, 2, or 4; or CV¹V² is C═V, wherein         V is O, NOR⁸⁰, or NNR⁸¹R⁸²;     -   R⁸⁰ is optionally substituted C₁-C₆ alkyl;     -   R⁸¹ and R⁸² independently are selected from the group consisting         of hydrogen, optionally substituted C₁-C₆ alkyl, COR⁸³, or         CO₂R⁸⁴;     -   R⁸³ is hydrogen or optionally substituted C₁-C₆ alkyl; and     -   R⁸⁴ is optionally substituted C₁-C₆ alkyl;     -   with the proviso that when ring C is C₆-C₁₀ aryl;     -   and ring B is optionally substituted 4-10 membered heterocyclyl;     -   then ring A excludes optionally substituted 5-10 membered         heteroaryl;     -   and provided that when ring C is C₆-C₁₀ aryl;     -   and ring B is optionally substituted 5-10 membered heteroaryl;     -   then ring A is not optionally substituted 4-10 membered         heterocycle.

In certain aspects of the invention, a compound of formula (X-I) is provided:

-   -   or a tautomer thereof, or a pharmaceutically acceptable salt of         each thereof, wherein     -   ring A is C₆-C₁₀ aryl, a C₃-C₈ cycloalkyl, a 5-10 membered         heteroaryl or a 4-10 membered heterocycle containing up to 5         ring heteroatoms, wherein the heteroatom is selected from the         group consisting of O, N, S, and oxidized forms of N and S,         wherein each of the aryl, heteroaryl, cycloalkyl, or heterocycle         is optionally substituted with 1-4: halo, C₁-C₆ alkyl, C₁-C₆         alkoxy, and/or C₃-C₁₀ cycloalkyl, wherein the C₁-C₆ alkyl is         optionally substituted with 1-5 halo, C₁-C₆ alkoxy, and/or         C₃-C₁₀ cycloalkyl;     -   ring B is a 5-10 membered heteroaryl or a 4-10 membered         heterocycle containing up to 5 ring heteroatoms, wherein the         heteroatom is selected from the group consisting of O, N, S, and         oxidized forms of N and S, wherein each of the heteroaryl and         the heterocycle is optionally substituted with 1-4: halo, C₁-C₆         alkyl and/or —CO—C₁-C₆ alkyl,     -   is a single or a double bond;     -   X is O, S, SO, or SO₂;     -   ring C is C₆-C₁₀ aryl or a 5-10 membered heteroaryl containing         up to 5 ring heteroatoms, wherein the heteroatom is selected         from the group consisting of O, N, S, and oxidized forms of N         and S, each of which is optionally substituted with 1-4: halo,         oxo, —OR¹, C₁-C₆ alkyl, —COOR¹, and/or C₁-C₆ alkoxy, wherein the         C₁-C₆ alkyl is optionally substituted with 1-5 halo, C₁-C₆         alkoxy and/or a 4-10 membered heterocycle containing up to 5         ring heteroatoms, wherein the heteroatom is selected from the         group consisting of O, N, S, and oxidized forms of N and S; and     -   R¹ is hydrogen or a prodrug moiety;     -   V¹ and V² independently are C₁-C₆ alkoxy; or V¹ and V² together         with the carbon atom they are attached to form a ring of         formula:

-   -   wherein each V³ and V⁴ are independently O, S, or NH, provided         that when one of V³ and V⁴ is S, the other is NH, and provided         that V³ and V⁴ are both not NH; q is 1 or 2; each V⁵ is         independently C₁-C₆ alkyl or CO₂R⁶⁰, where each R⁶⁰         independently is C₁-C₆ alkyl or hydrogen; t is 0, 1, 2, or 4; or         CV¹V² is C═V, wherein V is O, NOR⁸⁰, or NNR⁸¹R⁸²;     -   R⁸⁰ is optionally substituted C₁-C₆ alkyl;     -   R⁸¹ and R⁸² independently are selected from the group consisting         of hydrogen, optionally substituted C₁-C₆ alkyl, COR⁸³, or         CO₂R⁸⁴;     -   R⁸³ is hydrogen or optionally substituted C₁-C₆ alkyl;     -   R⁸⁴ is optionally substituted C₁-C₆ alkyl;     -   provided that when ring C is C₆-C₁₀ aryl;     -   and ring B is optionally substituted 4-10 membered heterocyclyl;     -   then ring A excludes optionally substituted 5-10 membered         heteroaryl;     -   and provided that when ring C is C₆-C₁₀ aryl;     -   and ring B is optionally substituted 5-10 membered heteroaryl;     -   then ring A is not optionally substituted 4-10 membered         heterocycle.

In certain aspects of the invention, a compound of formula (X-I) is provided:

-   -   or a tautomer thereof, or a pharmaceutically acceptable salt of         each thereof, wherein ring A is phenyl optionally substituted         with 1-3 halo and/or C₁-C₆ alkoxy, or is a 4-10 membered         heterocycle containing up to 3 ring heteroatoms, wherein the         heteroatom is selected from the group consisting of O, N, S, and         oxidized forms of N and S, optionally substituted, or is

-   -   -   wherein R is C₁-C₆ alkyl, optionally substituted with 3-3             fluoro groups, or is C₃-C₆ cycloalkyl;

    -   ring B is selected from the group consisting of

-   -   -   wherein R⁸ is C₁-C₆ alkyl, —CO—C₁-C₆ alkyl or a prodrug             moiety; X is O, S, SO, or SO₂;

    -   is a single or a double bond;

    -   ring C is phenyl or a 6 membered nitrogen-containing heteroaryl,         each of which is optionally substituted with 1-4: halo, oxo,         —OR¹, C₁-C₆ alkyl, —COOR¹, and/or C₁-C₆ alkoxy, wherein the         C₁-C₆ alkyl is optionally substituted with 1-3 halo, C₁-C₆         alkoxy and/or 4-10 membered heterocycle containing up to 3 ring         heteroatoms, wherein the heteroatom is selected from the group         consisting of O, N, S, and oxidized forms of N and S; and

    -   each R¹ is hydrogen or a prodrug moiety R;

    -   V¹ and V² independently are C₁-C₆ alkoxy; or V¹ and V² together         with the carbon atom they are attached to form a ring of         formula:

-   -   wherein each V³ and V⁴ are independently O, S, or NH, provided         that when one of V³ and V⁴ is S, the other is NH, and provided         that V³ and V⁴ are both not NH; q is 1 or 2; each V⁵ is         independently C₁-C₆ alkyl or CO₂R⁶⁰, where each R⁶⁰         independently is C₁-C₆ alkyl or hydrogen; t is 0, 1, 2, or 4; or         CV¹V² is C═V, wherein V is O, NOR⁸⁰, or NNR⁸¹R⁸²;     -   R⁸⁰ is optionally substituted C₁-C₆ alkyl;     -   R⁸¹ and R⁸² independently are selected from the group consisting         of hydrogen, optionally substituted C₁-C₆ alkyl, COR⁸³, or         CO₂R⁸⁴;     -   R⁸³ is hydrogen or optionally substituted C₁-C₆ alkyl;     -   R⁸⁴ is optionally substituted C₁-C₆ alkyl;     -   provided that when ring C is C₆-C₁₀ aryl;     -   and ring B is optionally substituted 4-10 membered heterocyclyl;     -   then ring A excludes optionally substituted 5-10 membered         heteroaryl;     -   and provided that when ring C is C₆-C₁₀ aryl;     -   and ring B is optionally substituted 5-10 membered heteroaryl;     -   then ring A is not optionally substituted 4-10 membered         heterocycle.

Preferably, V¹ and V² together with the carbon atom they are attached to form a ring of formula:

In some embodiments, V¹ and V² independently are C₁-C₆ alkoxy; or V¹ and V² together with the carbon atom they are attached to form a ring of formula:

wherein each V³ and V⁴ are independently O, S, or NH, provided that when one or V³ and V⁴ is S the other is NH, and provided that V³ and V⁴ are both not NH; q is 1 or 2; each V⁵ is independently C₁-C₆ alkyl or CO₂R⁶⁰, where each R⁶⁰ independently is C₁-C₆ alkyl or hydrogen; t is 0, 1, 2, or 4; or CV¹V² is C=V, wherein V is O, and wherein the remaining variables are defined herein.

In certain embodiments, a compound of formula (III) is provided:

-   -   or a tautomer thereof, or a pharmaceutically acceptable salt of         each thereof, wherein     -   ring A is phenyl optionally substituted with 1-3 halo and/or         C₁-C₆ alkoxy, or is a 4-10 membered heterocycle containing up to         3 ring heteroatoms, wherein the heteroatom is selected from the         group consisting of O, N, S, and oxidized forms of N and S,         optionally substituted, or is

-   -   -   wherein R⁷ is C₁-C₆ alkyl, optionally substituted with 3-3             fluoro groups, or is C₁-C₆ cycloalkyl;

    -   ring B is selected from the group consisting of

-   -   -   wherein R⁸ is C₁-C₆ alkyl, —CO—C₁-C₆ alkyl or a prodrug             moiety;

    -   X is O, S, SO, or SO₂;

    -   is a single or a double bond;

    -   ring C is phenyl or a 6 membered nitrogen-containing heteroaryl,         each of which is optionally substituted with 1-4: halo, oxo,         —OR¹, C₁-C₆ alkyl —COOR¹, and/or C₁-C₆ alkoxy, wherein the C₁-C₆         alkyl is optionally substituted with 1-5 halo, C₁-C₆ alkoxy         and/or 4-10 membered heterocycle containing up to 5 ring         heteroatoms, wherein the heteroatom is selected from the group         consisting of O, N, S, and oxidized forms of N and S; and

    -   each R¹ is hydrogen or a prodrug moiety R;

    -   V¹ and V² independently are C₁-C₆ alkoxy; or V¹ and V² together         with the carbon atom they are attached to form a ring of         formula:

-   -   wherein each V³ and V⁴ are independently O, S, or NH, provided         that when one of V³ and V⁴ is S, the other is NH, and provided         that V³ and V⁴ are both not NH; q is 1 or 2; each V⁵ is         independently C₁-C₆ alkyl or CO₂R⁶⁰, where each R⁶⁰         independently is C₁-C₆ alkyl or hydrogen; t is 0, 1, 2, or 4; or         CV¹V² is C═V, wherein V is O, NOR⁸⁰, or NNR⁸¹R⁸²;     -   R⁸⁰ is optionally substituted C₁-C₆ alkyl;     -   R⁸¹ and R⁸² independently are selected from the group consisting         of hydrogen, optionally substituted C₁-C₆ alkyl, COR⁸³, or         CO₂R⁸⁴;     -   R⁸³ is hydrogen or optionally substituted C₁-C₆ alkyl;     -   R⁸⁴ is optionally substituted C₁-C₆ alkyl;     -   provided that when ring C is C₆-C₁₀ aryl;     -   and ring B is optionally substituted 4-10 membered heterocyclyl;     -   then ring A excludes optionally substituted 5-10 membered         heteroaryl;     -   and provided that when ring C is C₆-C₁₀ aryl;     -   and ring B is optionally substituted 5-10 membered heteroaryl;     -   then ring A is not optionally substituted 4-10 membered         heterocycle.

In certain embodiments, t is 0. In certain embodiments, t is 1. In certain embodiments, t is 2. In certain embodiments, t is 3. In one embodiment, —X—Y— is —CH₂—O—. In another embodiment, —X—Y is —O—CH₂—.

In certain embodiments, a compound selected from formulas (IIIA), (IIIB) and (IIIC) is provided:

-   -   wherein     -   R⁹ is hydrogen, —OR¹, C₁-C₆ alkoxy optionally substituted with         1-3 C₁-C₆ alkoxy or 4-10 membered heterocycle containing up to 3         ring heteroatoms selected from N, O, S or oxidized forms         thereof;     -   R¹⁰ is hydrogen, halo, hydroxy or C₁-C₆ alkoxy;     -   R¹¹ is hydrogen or C₁-C₆ alkyl; and     -   R¹² is —OR¹;     -   wherein R¹ is hydrogen or the prodrug moiety R.

In certain embodiments, ring A is

-   -   phenyl substituted with 1-3 halo or C₁-C₆ alkoxy, or     -   C₃-C₈ heterocyclyl containing 1-3 heteroatoms, wherein the         heterocycle is optionally substituted with 1-3 halo.

In certain embodiments, ring A is pyridyl, optionally substituted as defined herein.

In certain embodiments, compounds of formulas (II), (III), (IIIA), (IIIB) and (IIIC) are provided, wherein

-   -   is selected from the group consisting of:

In certain embodiments, compounds of formulas (II), (III), (IIIA), (IIIB) and (IIIC) are provided, wherein

In certain embodiments, a compound is provided, wherein the compound selected from the group consisting of:

or an N oxides thereof, or a pharmaceutically acceptable salt of each thereof.

In certain embodiments, a compound is provided, wherein the compound selected from the group consisting of:

or an N oxides thereof, or a pharmaceutically acceptable salt of each thereof.

In certain aspects of the invention, a compound is provided, wherein the compound is selected from the group consisting of:

or a prodrug thereof, or a pharmaceutically acceptable salt of each thereof. Other compounds of this invention are illustrated in the Examples section.

In certain aspects of the invention, a compound of formula (I) is provided:

-   -   or a tautomer thereof, or a pharmaceutically acceptable salt of         each thereof, wherein L¹⁰ is optionally substituted methylene         or, preferably, a bond;     -   ring A is C₆-C₁₀ aryl, or a 5-10 membered heteroaryl, wherein         the heteroatom is selected from the group consisting of O, N, S,         and oxidized forms of N and S, wherein each of the aryl, or         heteroaryl is optionally substituted with 1-4 C₁-C₆ alkyl and/or         C₁-C₆ alkoxy groups;     -   ring B is:

-   -   wherein ring B′ including the —N—CO— moiety is a 5-6 membered         heterocycle containing up to 3 heteroatoms selected from         nitrogen, oxygen, and sulfur and oxidized forms of N and S,         wherein each of the heteroaryl and the heterocycle is optionally         substituted with 1-4 C₁-C₆ alkyl groups; each X and Y is         independently (CR²⁰R²¹)_(e), O, S, SO, SO₂, or NR²⁰; e is 1 to         4, preferably 1; each R²⁰ and R²¹ independently is hydrogen or         C₁-C₃ alkyl optionally substituted with 1-3 halo, OH, or C₁-C₆         alkoxy, or CR²⁰R²¹ is C═O, provided that if one of X and Y is O,         S, SO, SO₂, then the other is not CO, and X and Y are both not         heteroatoms or oxidized forms thereof;     -   ring C is C₆-C₁₀ aryl or a 5-10 membered heteroaryl containing         up to 5 ring heteroatoms, wherein the heteroatom is selected         from the group consisting of O, N, S, and oxidized forms of N         and S, each of which is optionally substituted with 1-4: halo,         oxo, —OR¹, C₁-C₆ alkyl, —COOR⁵, NR⁵R⁶,     -   R¹ is a hydrogen, C₁-C₆ alkyl or a prodrug moiety; wherein the         alkyl is optionally substituted with a 5-10 membered heteroaryl         containing up to 5 ring heteroatoms, wherein the heteroatom is         selected from the group consisting of O, N, S, and oxidized         forms of N and S, which is optionally substituted with with a         5-10 membered heteroaryl containing up to 5 ring heteroatoms,         wherein the heteroatom is selected from the group consisting of         O, N, S, and oxidized forms of N and S, wherein the heteroaryl         is optionally substituted with C₁-C₆ alkyl;     -   R⁵ and R⁶ are each independently hydrogen, optionally         substituted C₁-C₆ alkyl or —COOR³;     -   R³ is hydrogen or optionally substituted C₁-C₆ alkyl;     -   V¹ and V² independently are C₁-C₆ alkoxy; or V¹ and V² together         with the carbon atom they are attached to form a ring of         formula:

-   -   wherein each V³ and V⁴ are independently O, S, or NH, provided         that when one of V³ and V⁴ is S, the other is NH, and provided         that V³ and V⁴ are both not NH; q is 1 or 2; each V⁵ is         independently C₁-C₆ alkyl optionally substituted with 1-3 OH         groups, or V⁵ is CO₂R⁶⁰, where each R⁶⁰ independently is C₁-C₆         alkyl or hydrogen; t is 0, 1, 2, or 4; or CV¹V² is C=V, wherein         V is O, NOR⁸⁰, or NNR⁸¹R⁸²;     -   R⁸⁰ is optionally substituted C₁-C₆ alkyl;     -   R⁸¹ and R⁸² independently are selected from the group consisting         of hydrogen, optionally substituted C₁-C₆ alkyl, COR⁸³, or         CO₂R^(M);     -   R⁸³ is hydrogen or optionally substituted C₁-C₆ alkyl; and     -   R⁸⁴ is optionally substituted C₁-C₆ alkyl;     -   with the proviso that when ring C is C₆-C₁₀ aryl;     -   and ring B is optionally substituted 4-10 membered heterocyclyl;     -   then ring A excludes optionally substituted 5-10 membered         heteroaryl;     -   and provided that when ring C is C₆-C₁₀ aryl;     -   and ring B is optionally substituted 5-10 membered heteroaryl;     -   then ring A is not optionally substituted 4-10 membered         heterocycle.

In certain aspects of the invention, a compound of formula (IV) is provided:

-   -   or a tautomer thereof, or a pharmaceutically acceptable salt of         each thereof, wherein     -   ring A is C₆-C₁₀ aryl, or a 5-10 membered heteroaryl, wherein         the heteroatom is selected from the group consisting of O, N, S,         and oxidized forms of N and S, wherein each of the aryl or         heteroaryl is optionally substituted with 1-4 C₁-C₆ alkyl;     -   ring B is:

-   -   wherein ring B′ including the —N—CO— moiety is a 5-6 membered         heterocycle containing up to 3 heteroatoms selected from         nitrogen, oxygen, and sulfur and oxidized forms of N and S,         wherein each of the heteroaryl and the heterocycle is optionally         substituted with 1-4 C₁-C₆ alkyl groups;     -   each X and Y is independently CR²⁰R²¹, O, S, SO, SO₂, or NR¹⁰;         each R²⁰ and R²¹ independently is hydrogen or C₁-C₃ alkyl         optionally substituted with 1-3 halo, OH, or C₁-C₆ alkoxy, or         CR²⁰R²¹ is C═O, provided that if one of X and Y is O, S, SO,         SO₂, then the other is not CO, and X and Y are both not         heteroatoms or oxidized forms thereof;     -   ring C is C₆-C₁₀ aryl or a 5-10 membered heteroaryl containing         up to 5 ring heteroatoms, wherein the heteroatom is selected         from the group consisting of O, N, S, and oxidized forms of N         and S, each of which is optionally substituted with 1-4: halo,         oxo, —OR¹, C₁-C₆ alkyl, —COOR⁵, NR⁵R⁶,     -   R¹ is a hydrogen, C₁-C₆ alkyl or a prodrug moiety; wherein the         alkyl is optionally substituted with a 5-10 membered heteroaryl         containing up to 5 ring heteroatoms, wherein the heteroatom is         selected from the group consisting of O, N, S, and oxidized         forms of N and S, which is optionally substituted with with a         5-10 membered heteroaryl containing up to 5 ring heteroatoms,         wherein the heteroatom is selected from the group consisting of         O, N, S, and oxidized forms of N and S, wherein the heteroaryl         is optionally substituted with C₁-C₆ alkyl;     -   R⁵ and R⁶ are each independently hydrogen, optionally         substituted C₁-C₆ alkyl or —COOR³;     -   R³ is hydrogen or optionally substituted C₁-C₆ alkyl;     -   V¹ and V² independently are C₁-C₆ alkoxy; or V¹ and V² together         with the carbon atom they are attached to form a ring of         formula:

-   -   wherein each V³ and V⁴ are independently O, S, or NH, provided         that when one of V³ and V⁴ is S, the other is NH, and provided         that V³ and V⁴ are both not NH; q is 1 or 2; each V⁵ is         independently C₁-C₆ alkyl optionally substituted with 1-3 OH         groups, or V⁵ is CO₂R⁶⁰, where each R⁶⁰ independently is C₁-C₆         alkyl or hydrogen; t is 0, 1, 2, or 4; or CV¹V² is C═V, wherein         V is O, NOR⁸⁰, or NNR⁸¹R⁸²;     -   R⁸⁰ is optionally substituted C₁-C₆ alkyl;     -   R⁸¹ and R⁸² independently are selected from the group consisting         of hydrogen, optionally substituted C₁-C₆ alkyl, COR⁸³, or         CO₂R⁸⁴;     -   R⁸³ is hydrogen or optionally substituted C₁-C₆ alkyl; and     -   R⁸⁴ is optionally substituted C₁-C₆ alkyl.

In certain embodiments, ring C is substituted with at least one substituent selected from with 1-4: halo, —OR¹, C₁-C₆ alkyl, —COOR⁵, NR⁵R⁶.

In certain embodiments, X is CH₂, O, S, SO, SO₂ or NH. In certain embodiments, X is O, S, SO or SO₂. Preferably, X is O, and wherein the remaining variables are defined herein.

In certain embodiments, Y is CR²⁰R²¹, O, S, SO, SO₂ or NR¹⁰; wherein each R²⁰ and R²¹ independently is hydrogen or C₁-C₃ alkyl. In certain embodiments, Y is CR²⁰R²¹ wherein each R²⁰ and R²¹ independently is hydrogen or C₁-C₃ alkyl. Preferably, Y is CH₂, and wherein the remaining variables are defined herein.

In certain embodiments, t is 0. In certain embodiments, t is 1. In certain embodiments, t is 2. In certain embodiments, t is 3.

Preferably, CV¹V² is C═V, wherein V is O, and wherein the remaining variables are defined herein.

In certain embodiments, a compound of formula (V) is provided:

-   -   or a tautomer thereof, or a pharmaceutically acceptable salt of         each thereof, wherein     -   ring A is C₆-C₁₀ aryl, or a 5-10 membered heteroaryl, wherein         the heteroatom is selected from the group consisting of O, N, S,         and oxidized forms of N and S, wherein each of the aryl, or         heteroaryl is optionally substituted with 1-4 C₁-C₆ alkyl and/or         C₁-C₆ alkoxy groups;     -   ring B is:

-   -   wherein ring B′ including the —N—CO— moiety is a 5-6 membered         heterocycle containing up to 3 heteroatoms selected from         nitrogen, oxygen, and sulfur and oxidized forms of N and S,         wherein each of the heteroaryl and the heterocycle is optionally         substituted with 1-4 C₁-C₆ alkyl groups;     -   X is O, S, SO or SO₂;     -   ring C is C₆-C₁₀ aryl or a 5-10 membered heteroaryl containing         up to 5 ring heteroatoms, wherein the heteroatom is selected         from the group consisting of O, N, S, and oxidized forms of N         and S, each of which is optionally substituted with 1-4: halo,         oxo, —OR¹, C₁-C₆ alkyl, —COOR⁵, NR⁵R⁶,     -   R¹ is a hydrogen, C₁-C₆ alkyl or a prodrug moiety R; wherein the         alkyl is optionally substituted with a 5-10 membered heteroaryl         containing up to 5 ring heteroatoms, wherein the heteroatom is         selected from the group consisting of O, N, S, and oxidized         forms of N and S, which is optionally substituted with with a         5-10 membered heteroaryl containing up to S ring heteroatoms,         wherein the heteroatom is selected from the group consisting of         O, N, S, and oxidized forms of N and S, wherein the heteroaryl         is optionally substituted with C₁-C₆ alkyl;     -   R⁵ and R⁶ are each independently hydrogen, optionally         substituted C₁-C₆ alkyl or —COOR³; and     -   R³ is hydrogen or optionally substituted C₁-C₆ alkyl.

In certain embodiments, a compound of formula (VI) or (VII) is provided:

-   -   or a tautomer thereof, or a pharmaceutically acceptable salt of         each thereof, wherein     -   ring A is C₆-C₁₀ aryl, or a 5-10 membered heteroaryl, wherein         the heteroatom is selected from the group consisting of O, N, S,         and oxidized forms of N and S, wherein each of the aryl, or         heteroaryl is optionally substituted with 1-4 C₁-C₆ alkyl;     -   ring B is C₆-C₁₀ aryl, C₃-C₈ cycloalkyl, a 5-10 membered         heteroaryl containing up to 5 ring heteroatoms or a 4-10         membered heterocycle containing up to 5 ring heteroatoms,         wherein the heteroatom is selected from the group consisting of         O, N, S, and oxidized forms of N and S, wherein each of the         aryl, heteroaryl, cycloalkyl or heterocycle is optionally         substituted with 1-4: halo, C₁-C₆ alkyl, or C₁-C₆ alkoxy,         wherein the C₁-C₆ alkyl is optionally substituted with 1-5 halo,         C₁-C₆ alkoxy, and/or C₃-C₁₀ cycloalkyl;     -   R⁴ is halo, oxo, —OR¹⁸, C₁-C₆ alkyl, C₁-C₆ alkoxy, —COOR⁵,         and/or NR⁵R⁶;     -   R¹⁸ is hydrogen, substituted C₁-C₆ alkyl, or a prodrug moiety R;     -   R⁵ and R⁶ are each independently hydrogen, optionally         substituted C₁-C₆ alkyl or —COOR³; and     -   R³ is hydrogen, provided that the COOR³ is not joined to a         nitrogen atom, or is optionally substituted C₁-C₆ alkyl.

In one embodiment, R⁴ is —OH. In another embodiment, R⁴ is NH₂. In one embodiment, R⁴ is NH(CH₃). In one embodiment, R⁴ is N(CH₃)₂. In one embodiment, R⁴ is NHC(O)OC(CH₃)₃. In one embodiment, R⁴ is COOH. In one embodiment, R⁴ is optionally substituted dioxolan. In one embodiment, R⁴ is a substituted pyridine. As used herein, R³ is hydrogen, provided that the COOR³ is not joined to a nitrogen atom.

In certain embodiments, ring B is selected from the group consisting of:

In certain embodiments, compounds of formula (V) are provided, wherein

In certain embodiments, a compound of formula (IV) as disclosed above is provided, with the proviso that:

-   -   when ring C is C₆-C₁₀ aryl;     -   and ring B is optionally substituted 4-10 membered heterocyclyl;     -   then ring A excludes optionally substituted 5-10 membered         heteroaryl.

In certain embodiments, a compound is provided, wherein the compound is selected from the group consisting of:

or N oxides thereof, or a pharmaceutically acceptable salt of each thereof.

Compounds provided herein include those in the Examples section.

Prodrug Moiety

In one aspect, R is hydrogen, a phosphate or a diphosphate containing moiety, or another promoiety or prodrug moiety. Preferably the prodrug moiety imparts at least a 2 fold, more preferably a 4 fold, enhanced solubility and/or bioavailability to the active moiety (where R is hydrogen), and more preferably is hydrolyzed in vivo. The promoieties are structurally and functionally defined herein.

In one embodiments, R is —COR⁹⁰, CO₂R⁹¹, or CONR⁹²R⁹³ wherein

R⁹⁰ and R⁹¹ independently are C₁-C₆ alkyl, C₃-C₈ cycloalkyl, 4-9 membered heterocycle, or a 5-10 membered heteroaryl, each containing at least 1 basic nitrogen moiety; and R⁹² and R⁹³ independently are C₁-C₆ alkyl; C₃-C₈ cycloalkyl, 4-9 membered heterocycle, or a 5-10 membered heteroaryl, each containing at least 1 basic nitrogen moiety; or R⁹² and R⁹³ together with the nitrogen atom they are bonded to for a 4-9 member heterocycle substituted with at least 1 amino, C₁-C₆ alkyl amino, or di C₁-C₆ alkylamino group.

In certain embodiments, R is —C(O)R³¹, C(O)OR³¹, or CON(R¹³)₂,

-   -   each R³¹ is independently a C₁-C₆ alkyl; C₃-C₈ cycloalkyl, 4-9         membered heterocycle, or a 5-10 membered heteroaryl, containing         at least 1 basic nitrogen moiety; and     -   each R¹³ independently is C₁-C₆ alkyl; C₃-C₈ cycloalkyl, 4-9         membered heterocycle, or a 5-10 membered heteroaryl, containing         at least 1 basic nitrogen moiety; or both R¹³ together with the         nitrogen atom they are bonded to for a 4-9 member heterocycle         substituted with at least 1 amino, C₁-C₆ alkyl amino, or di         C₁-C₆ alkylamino group.

In one aspect, R is C(O)OR³¹, C(S)OR³¹, C(O)SR³¹ or COR³¹, wherein R³¹ is as defined herein.

In one embodiment, R³¹ is a group of the formula (CR³²R³³)_(e)NR³⁴R³⁵, wherein each R³² and R³³ is independently H, a C₁-C₈ alkyl, C₃-C₉ heterocyclyl, C₃-C₈ cycloalkyl, C₆-C₁₀ aryl, C₃-C₉ heteroaryl or R³² and R³³ together with the carbon atom they are bond to form a C₃-C₈ cycloalkyl, C₆-C₁₀ aryl, C₃-C₉ heterocyclyl or C₃-C₉ heteroaryl ring system, or 2 adjacent R³² moieties or 2 adjacent R³³ moieties together with the carbon atom they are bond to form a C₃-C₈ cycloalkyl, C₆-C₁₀ aryl, C₃-C₉ heterocyclyl or C₃-C₉ heteroaryl ring system;

-   -   each R³⁴ and R³⁵ is a C₁-C₈ alkyl, C₃-C₉ heterocyclyl, C₃-C₈         cycloalkyl, or R³⁴ and R³⁵ together with the nitrogen atom they         are bond to form a C₃-C₈ cycloalkyl or C₃-C₉ heterocyclyl ring         system;     -   each heterocyclic and heteroaryl ring system is optionally         substituted with C₁-C₃ alkyl, —OH, amino and carboxyl groups;         and     -   e is an integer of from 1 to 4.

In some less preferred embodiments R³⁴ and R³⁵ can be hydrogen.

In one embodiment, the subscript e is preferably 2 and each R³² and R³³ is preferably independently selected from the group, H, CH₃, and a member in which R³² and R³³ are joined together to form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or 1,1-dioxo-hexahydro-1Δ⁶-thiopyran-4-yl or tetrahydropyran-4-yl group.

With regard to the prodrug group, preferred embodiments are compounds wherein NR³⁴R³⁵ is morpholino.

In one embodiment, R is:

wherein

each R³² and R³³ is independently H, C₁-C₈ alkyl, or optionally, if both present on the same substituent, may be joined together to form a C₃-C₈ cycloalkyl, C₆-C₁₀ aryl, C₃-C₉ heterocyclyl or C₃-C₉ heteroaryl ring system.

Within this embodiment, each R³² and R³³ is independently, H, CH₃, or are joined together to form a cyclopropyl, cyclopbutyl, cyclopentyl, cyclohexyl, 1,1-dioxo-hexahydro-1λ⁶-thiopyran-4-yl or tetrahydropyran-4-yl group.

In a preferred embodiment, linkage of the prodrug moiety to the rest of the active molecule is stable enough so that the serum half life of the prodrug is from about 8 to about 24 hours.

In an embodiment of the invention, the prodrug moiety comprises a tertiary amine having a pKa near the physiological pH of 7.3. Any amines having a pKa within 1 unit of 7.3 are suitable alternatives amines for this purpose. The amine may be provided by the amine of a morpholino group. This pKa range of 6.3 to 8.3 allows for significant concentrations of the basic neutral amine to be present in the mildly alkaline small intestine. The basic, neutral form of the amine prodrug is lipophilic and is absorbed through the wall of the small intestine into the blood. Following absorption into the bloodstream, the prodrug moiety is cleaved by esterases which are naturally present in the serum to release an active compound.

Examples of R include, without limitation:

In another embodiment, R is as tabulated below:

R m R³⁴ R³⁵ NR³⁴R³⁵ C(O)(CH₂)_(m)NR³⁴R³⁵ 1 Me Me C(O)(CH₂)_(m)NR³⁴R³⁵ 2 Me Me C(O)(CH₂)_(m)NR³⁴R³⁵ 3 Me Me C(O)(CH₂)_(m)NR³⁴R³⁵ 4 Me Me C(O)(CH₂)_(m)NR³⁴R³⁵ 1

C(O)(CH₂)_(m)NR³⁴R³⁵ 2

C(O)(CH₂)_(m)NR³⁴R³⁵ 3

C(O)(CH₂)_(m)NR³⁴R³⁵ 4

C(O)O(CH₂)_(m)NR³⁴R³⁵ 2 Me Me C(O)O(CH₂)_(m)NR³⁴R³⁵ 3 Me Me C(O)O(CH₂)_(m)NR³⁴R³⁵ 4 Me Me C(O)O(CH₂)_(m)NR³⁴R³⁵ 2

C(O)O(CH₂)_(m)NR³⁴R³⁵ 3

C(O)O(CH₂)_(m)NR³⁴R³⁵ 4

P(O)(OH)₂ an N oxide thereof, or a pharmaceutically acceptable salt of each thereof.

In another aspect, R is,

wherein

R³⁶ is lower alkyl (e.g. C₁-C₆ alkyl).

In yet another aspect, R is:

wherein X¹, Y¹ and X² are as defined herein.

In one embodiment, X¹ is selected from the group consisting of O, S and NR³⁷ wherein R³⁷ is hydrogen or C₁-C₆ alkyl;

Y¹ is —C(R³⁸)₂ or a sugar moiety, wherein each R³⁸ is independently hydrogen or C₁-C₆ alkyl, C₃-C₈ cycloalkyl, C₃-C₉ heterocyclyl, C₆-C₁₀ aryl, or C₃-C₉ heteroaryl;

X² is selected from the group consisting of halogen, C₁-C₆ alkoxy, diacylglycerol, amino, C₁-C₆ alkylamino, C₁-C₆ dialkylamino, C₁-C₆ alkylthio, a PEG moiety, a bile acid moiety, a sugar moiety, an amino acid moiety, a di- or tri-peptide, a PEG carboxylic acid, and —U—V wherein

U is O or S; and

V is selected from the group consisting of C₁-C₆ alkyl, C₃-C₈ cycloalkyl, C₃-C₉ heterocyclyl, C₆-C₁₀ aryl, C₃-C₉ heteroaryl, C(W²)X³, PO(X³)₂, and SO₂X³;

wherein W² is O or NR³⁹

wherein R³⁹ is hydrogen or C₁-C₆ alkyl, C₃-C₈ cycloalkyl, C₃-C₉ heterocyclyl, C₆-C₁₀ aryl, or C₃-C₉ heteroaryl; and

each X³ is independently amino, hydroxyl, mercapto, C₁-C₆ alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, C₁-C₆ alkoxy, C₁-C₆ alkylamino, C₁-C₆ dialkylamino, C₁-C₆ alkylthio, a bile acid based alkoxy group, a sugar moiety, a PEG moiety, and —O—CH₂—CH(OR⁴⁰)CH₂X⁴R⁴⁰,

wherein:

X⁴ is selected from the group consisting of O, S, S═O, and SO₂; and

each R⁴⁰ is independently C₁₀-C₂₂ alkyl, C₃-C₈ cycloalkyl, C₃-C₉ heterocyclyl, C₆-C₁₀ aryl, or C₃-C₉ heteroaryl, C₁-C₈ alkylene, or C₁-C₈ heteroalkylene.

Each heterocyclic and heteroaryl ring system is optionally substituted with C₁-C₃ alkyl, —OH, amino and carboxyl groups.

In one embodiment, the present invention utilizes the following Y¹ groups: CH₂, CHMe, CH(isopropyl), CH(tertiarybutyl), C(Me)₂, C(Et)₂, C(isopropyl)₂, and C(propyl)₂.

In another embodiment, the present invention utilizes the following X² groups:

—OMe, —OEt, —O-isopropyl, O-isobutyl, O-tertiarybutyl, —O—COMe, —O—C(═O)(isopropyl), —O—C(═O)(isobutyl), —O—C(═O)(tertiarybutyl), —O—C(═O)—NMe₂, —O—C(═O)—NHMe, —O—C(═O)—NH₂, —O—C(═O)—N(H)—CH(R⁴¹)—CO₂Et wherein R⁴¹ is a side chain C₁-C₆ alkyl, or C₃-C₉ heterocyclyl group selected from the side chain groups present in essential amino acids; —O—P(═O)(OMe)₂, —O—P(═O)(O-isopropyl)₂, and —O—P(=O)(O-isobutyl)₂. Each heterocyclic is optionally substituted with one or more, preferably, 1-3, C₁-C₃ alkyl, —OH, amino and/or carboxyl groups.

In another embodiment, In one embodiment, R is:

wherein

X³ is independently C₁-C₆ alkyl, C₃-C₈ cycloalkyl, C₃-C₉ heterocyclyl, C₆-C₁₀ aryl, or C₃-C₉ heteroaryl; and

-   -   R⁴² is independently hydrogen or C₁-C₆ alkyl, C₃-C₈ cycloalkyl,         C₃-C₉ heterocyclyl, C₆-C₁₀ aryl, or C₃-C₉ heteroaryl.

Each heterocyclic is optionally substituted with one or more, preferably, 1-3, C₁-C₃ alkyl, —OH, amino and/or carboxyl groups.

In one embodiment, R is:

wherein

each X³ is independently amino, hydroxyl, mercapto, C₁-C₆ alkyl, C₃-C₈ cycloalkyl, C₃-C₉ heterocyclyl, C₆-C₁₀ aryl, or C₃-C₉ heteroaryl, C₁-C₆ alkoxy, C₁-C₆ alkylamino, C₁-C₆ dialkylamino, C₁-C₆ alkylthio, a bile acid based alkoxy group, a sugar moiety, a PEG moiety, and —O—CH₂—CH(OR⁴⁰)CH₂X⁴R⁴⁰,

wherein:

X⁴ is selected from the group consisting of O, S, S═O, and SO₂; and

each R⁴⁰ is independently C₁₀-C₂₂ alkyl, C₃-C₈ cycloalkyl, C₃-C₉ heterocyclyl, C₆-C₁₀ aryl, C₃-C₉ heteroaryl, C₁-C₈ alkylene, or C₁-C₈ heteroalkylene; and

R⁴² is independently hydrogen or C₁-C₆ alkyl, C₃-C₈ cycloalkyl, C₃-C₉ heterocyclyl, C₆-C₁₀ aryl, or C₃-C₉ heteroaryl.

In some embodiments, R⁴² is independently hydrogen or C₁-C₆ alkyl, C₃-C₈ cycloalkyl, C₃-C₉ heterocyclyl, C₆-C₁₀ aryl, or C₃-C₉ heteroaryl; and each X³ independently is C₁-C₆ alkyl, C₃-C₈ cycloalkyl, C₃-C₉ heterocyclyl, C₆-C₁₀ aryl, or C₃-C₉ heteroaryl, C₁-C₆ alkoxy, C₁-C₆ alkylamino, C₁-C₆ dialkylamino, or C₁-C₆ alkylthio.

In some embodiments, R is represented by the following structures:

wherein, in the above examples, R⁴³ is C₁₀-C₂₂ alkyl or alkylene, R⁴⁴ is H or C₁-C₆ alkyl and R⁴⁵ represents side chain alkyl groups present in naturally occurring alpha amino acids;

wherein R⁴⁶ is (CH₂)_(n), f=2-4, and CO—R⁴⁷—NH₂ represents an aminoacyl group; or

wherein R⁴⁶ is (CH₂)_(n), n=2-4, R⁴⁷ is (CH₂)_(n), n=1-3 and R⁴⁹ is O or NMe.

In one embodiment, R is:

In one aspect, R is —C(R²⁰⁰R²⁰¹)O(R²⁰²R²⁰³)P(O)OR²⁰⁴NR²⁰⁵R²⁰⁶, wherein each R²⁰⁰, R²⁰¹, R²⁰², R²⁰³, R²⁰⁴ R²⁰⁵ and R²⁰⁶ is independently H, a C₁-C₈ alkyl, C₃-C₉ heterocyclyl, C₃-C₈ cycloalkyl, C₆-C₁₀ aryl, C₃-C₉ heteroaryl, wherein each alkyl, heterocyclyl, cycloalkyl, aryl, and heteroaryl is optionally substituted.

In some embodiments, R is —CH(R²⁰¹)OCH₂P(O)OR²⁰⁴NHR²⁰⁶, wherein R²⁰¹ is C₁-C₈ alkyl, R²⁰⁴ is phenyl, optionally substituted. In one embodiment, R²⁰⁶ is —CHR²⁰⁷C(O)OR²⁰⁸ wherein R²⁰⁷ is selected from the group consisting of the naturally occurring amino acid side chains and —CO₂H esters thereof and R²⁰⁸ is C₁-C₈ alkyl. In one embodiment, R²⁰⁶ is C₁-C₆ alkyl, optionally substituted with 1-3, CO₂H, SH, NH₂, C₆-C₁₀ aryl, and C₂-C₁₀ heteroaryl.

In one embodiment, R is:

In one embodiment, R is:

wherein Y¹ is —C(R³⁸)₂ wherein each R³⁸ is independently hydrogen or C₁-C₆ alkyl, C₃-C₈ cycloalkyl, C₃-C₉ heterocyclyl, C₆-C₁₀ aryl, or C₃-C₉ heteroaryl.

Various polyethylene glycol (PEG) moieties and synthetic methods related to them that can be used or adapted to make compounds of the invention are described in U.S. Pat. Nos. 6,608,076; 6,395,266; 6,194,580; 6,153,655; 6,127,355; 6,111,107; 5,965,566; 5,880,131; 5,840,900; 6,011,042 and 5,681,567.

In one embodiment, R is

wherein

R⁵⁰ is —OH or hydrogen;

R⁵¹ is —OH, or hydrogen;

W is —CH(CH₃)W¹;

wherein W¹ is a substituted C₁-C₈ alkyl group containing a moiety which is optionally negatively charged at physiological pH,

said moiety is selected from the group consisting of CO₂H, SO₃H, SO₂H, —P(O)(OR⁵²)(OH), —OP(O)(OR⁵²)(OH), and OSO₃H,

wherein R⁵² is C₁-C₆ alkyl, C₃-C₈ cycloalkyl, C₃-C₉ heterocyclyl, C₆-C₁₀ aryl, or C₃-C₉ heteroaryl.

Each heterocyclic and heteroaryl ring system is optionally substituted with one or more, preferably 1-3, C₁-C₃ alkyl, —OH, amino and/or carboxyl groups.

In one embodiment, R is:

wherein R⁵³ is H or C₁-C₆ alkyl.

In another aspect, R is SO₃H.

In another aspect, R comprises a cleavable linker, wherein the term “cleavable linker” refers to a linker which has a short half life in vivo. The breakdown of the linker Z in a compound releases or generates the active compound. In one embodiment, the cleavable linker has a half life of less than ten hours. In one embodiment, the cleavable linker has a half life of less than an hour. In one embodiment, the half life of the cleavable linker is between one and fifteen minutes. In one embodiment, the cleavable linker has at least one connection with the structure: C*—C(═X*)X*—C* wherein C* is a substituted or unsubstituted methylene group, and X* is S or O. In one embodiment, the cleavable linker has at least one C*—C(═O)O—C* connection. In one embodiment, the cleavable linker has at least one C*—C(═O)S—C* connection. In one embodiment, the cleavable linker has at least one —C(═O)N*—C*—SO₂—N*-connection, wherein N* is —NH— or C₁-C₆ alkylamino. In one embodiment, the cleavable linker is hydrolyzed by an esterase enzyme.

In one embodiment, the linker is a self-immolating linker, such as that disclosed in U.S. patent publication 2002/0147138, to Firestone; PCT Appl. No. US03/08161 and PCT Pub. No. 2004/087073. In another embodiment, the linker is a substrate for enzymes. See generally Rooseboom et al., 2004, Pharmacol. Rev. 36:33-102.

Pharmaceutical Compositions

In further aspects of the invention, a composition is provided comprising any of the compounds described herein, and at least a pharmaceutically acceptable excipient.

In another aspect, this invention provides a composition comprising any of the compounds described herein, and a pharmaceutically acceptable excipient.

Such compositions can be formulated for different routes of administration. Although compositions suitable for oral delivery will probably be used most frequently, other routes that may be used include transdermal, intravenous, intraarterial, pulmonary, rectal, nasal, vaginal, lingual, intramuscular, intraperitoneal, intracutaneous, intracranial, and subcutaneous routes. Suitable dosage forms for administering any of the compounds described herein include tablets, capsules, pills, powders, aerosols, suppositories, parenterals, and oral liquids, including suspensions, solutions and emulsions. Sustained release dosage forms may also be used, for example, in a transdermal patch form. All dosage forms may be prepared using methods that are standard in the art (see e.g., Remington's Pharmaceutical Sciences, 16th ed., A. Oslo editor, Easton Pa. 1980).

Pharmaceutically acceptable excipients are non-toxic, aid administration, and do not adversely affect the therapeutic benefit of the compound of this invention. Such excipients may be any solid, liquid, semi-solid or, in the case of an aerosol composition, gaseous excipient that is generally available to one of skill in the art. Pharmaceutical compositions in accordance with the invention are prepared by conventional means using methods known in the art.

The compositions disclosed herein may be used in conjunction with any of the vehicles and excipients commonly employed in pharmaceutical preparations, e.g., talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous or non-aqueous solvents, oils, paraffin derivatives, glycols, etc. Coloring and flavoring agents may also be added to preparations, particularly to those for oral administration. Solutions can be prepared using water or physiologically compatible organic solvents such as ethanol, 1,2-propylene glycol, polyglycols, dimethylsulfoxide, fatty alcohols, triglycerides, partial esters of glycerin and the like.

Solid pharmaceutical excipients include starch, cellulose, hydroxypropyl cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, dried skim milk and the like. Liquid and semisolid excipients may be selected from glycerol, propylene glycol, water, ethanol and various oils, including those of petroleum, animal, vegetable or synthetic origin, e.g., peanut oil, soybean oil, mineral oil, sesame oil, etc. In certain embodiments, the compositions provided herein comprises one or more of α-tocopherol, gum arabic, and/or hydroxypropyl cellulose.

In one embodiment, this invention provides sustained release formulations such as drug depots or patches comprising an effective amount of a compound provided herein. In another embodiment, the patch further comprises gum Arabic or hydroxypropyl cellulose separately or in combination, in the presence of alpha-tocopherol. Preferably, the hydroxypropyl cellulose has an average MW of from 10,000 to 100,000. In a more preferred embodiment, the hydroxypropyl cellulose has an average MW of from 5,000 to 50,000.

Compounds and pharmaceutical compositions of this invention maybe used alone or in combination with other compounds. When administered with another agent, the co-administration can be in any manner in which the pharmacological effects of both are manifest in the patient at the same time. Thus, co-administration does not require that a single pharmaceutical composition, the same dosage form, or even the same route of administration be used for administration of both the compound of this invention and the other agent or that the two agents be administered at precisely the same time. However, co-administration will be accomplished most conveniently by the same dosage form and the same route of administration, at substantially the same time. Obviously, such administration most advantageously proceeds by delivering both active ingredients simultaneously in a novel pharmaceutical composition in accordance with the present invention.

Methods of Treatment

In aspects of the invention, a method is provided for increasing tissue and/or cellular oxygenation, the method comprising administering to a subject in need thereof a therapeutically effective amount of any of the compounds or compositions described herein.

In aspects of the invention, a method is provided for increasing oxygen affinity of hemoglobin S in a subject, the method comprising administering to a subject in need thereof a therapeutically effective amount of any of the compounds or compositions described herein.

In aspects of the invention, a method is provided for treating a condition associated with oxygen deficiency, the method comprising administering to a subject in need thereof a therapeutically effective amount of any of the compounds or compositions described herein.

In further aspects of the invention, a method is provided for treating oxygen deficiency associated with sickle cell anemia, the method comprising administering to a subject in need thereof a therapeutically effective amount of any of the compounds or compositions described herein.

In further aspects of the invention, a method is provided for treating sickle cell disease, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any of the compounds or compositions described herein. In still further aspects of the invention, a method is provided for treating cancer, a pulmonary disorder, stroke, high altitude sickness, an ulcer, a pressure sore, Alzheimer's disease, acute respiratory disease syndrome, and a wound, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any of the compounds or compositions described herein.

Synthetic Methods

Certain methods for making the compounds described herein are also provided. The reactions are preferably carried out in a suitable inert solvent that will be apparent to the skilled artisan upon reading this disclosure, for a sufficient period of time to ensure substantial completion of the reaction as observed by thin layer chromatography, ¹H-NMR, etc. If needed to speed up the reaction, the reaction mixture can be heated, as is well known to the skilled artisan. The final and the intermediate compounds are purified, if necessary, by various art known methods such as crystallization, precipitation, column chromatography, and the likes, as will be apparent to the skilled artisan upon reading this disclosure.

An illustrative and non-limiting method for synthesizing a compound of formula (I), is schematically shown below.

In the following Schemes,

refer to rings A, B and C as described herein;

A⁵ and B⁵ are independently NR¹⁴, O, S, S(O)x, NBoC, CH₂, CHR¹⁴, C(R¹⁴)₂ provided that when both A⁵ and B⁵ are present in a ring, both are not CH₂, CHR¹⁴, C(R¹⁴)₂, and that when only 1 A⁵ or B⁵ is present in a ring the A⁵ or B⁵ is not CH₂, CHR¹⁴, C(R¹⁴)₂;

R¹⁴ is C₁-C₆ alkyl, COR¹⁵ or COOR¹⁵; wherein R¹⁵ is optionally substituted C₁-C₆ alkyl, optionally substituted C₆-C₁₀ aryl, optionally substituted 5-10 membered heteroaryl containing up to 5 ring heteroatoms, or optionally substituted 4-10 membered heterocycle containing up to 5 ring heteroatoms, wherein the heteroatom is selected from the group consisting of O, N, S, and oxidized forms of N and S;

X, and X⁵ each represents a leaving group and are independently selected from Cl, Br, and I.

X⁶ represents CR, N, O, S(O)x; wherein x is 0, 1, or 2;

R⁷¹ is C₁-C₆ alkyl;

Y⁵ represents a leaving group selected from Cl, F, Br, I, OSO₂R¹⁷ and OSO₂Ar;

Ar is phenyl optionally substituted with 1-3 halo and/or C₁-C₄ alkyl;

n is 0, 1, or 2; and

Where variables already used in the structures hereinabove are used in the schemes, the context makes it unambiguous as to what the variable refers to.

General Synthetic Schemes

General method A (Scheme 1) for preparing aryloxy/heteroarylether analogs (4a/4b) from substituted methylene alcohol (1) and hydroxyl (hetero)aryl aldehyde derivatives (3a/3b). A hydroxyl (hetero)aryl aldehyde derivatives (3a/3b) (0.1-2 mmol) mixture with substituted methylene alcohol (1) (0.8 to 1.2 eq) and PPh₃ (1-1.5 eq) in anhydrous THF (1-10 mL) was stirred under nitrogen until complete dissolution. The solution was cooled to 0° C. on ice bath and DIAD or DEAD (1.1 eq) in THF or toluene was added dropwise over a 1-20 min period. The ice cooling bath was allowed to expire over 90 min and the mixture was stirred at RT for 2-48 hours. The mixture was stirred for 10 min, then filtered through a pad of silica. The silica was washed with ethyl acetate 2-20 mL. The combined filtrates were evaporated and the residue was dried on highvac. The residue was purified by preparative HPLC or flash silica gel chromatography.

General method A (Scheme 1) for preparing aryloxy/heteroarylether analogs (4a/4b) from substituted methylene halide (2) and hydroxyl (hetero)aryl aldehyde derivatives (3a/3b). A mixture of hydroxyl (hetero)arylaldehyde derivatives (3a/3b) (0.1-2 mmol, 1-4 eq.), substituted methylene chloride or bromide (2) (1 eq), and K₂CO₃ (2-5 eq.) (catalytic amount of NaI or Bu₄NI may also be added) in DMF or acetonitrile (1 to 10 mL) was stirred at RT or heating up to 120° C. for 0.5-8 h under nitrogen atmosphere. In workup A, water was added to the reaction mixture, the precipitated product was collected, washed with water, and then subjected to preparative HPLC or flash silica gel chromatography purification. In workup B (for products that did not precipitate), diluted HCl or aqueous NR₄Cl was added at 0° C. to adjusted the pH to ˜7, the reaction mixture was partitioned between ethyl acetate or dichloromethane and aqueous sodium chloride and the organic layer separated, dried, and solvent removed under vacuum to afford crude product which was purified by automated silica gel column chromatography using appropriate solvents mixture (e.g., ethyl acetate/hexanes).

General method C for preparing substituted methylene chloride (2a). To a solution of substituted methylene alcohol (1) (0.1 to 2 mmol) in DCM (1-10 mL) was added SOCl₂ dropwise (2 eq to 5 eq) at 0° C. or RT. The reaction mixture was stirred at RT for 10 min to 6 h, or until reaction is judged complete (LC/MS). The reaction mixture is concentrated to dryness over a rotavap. The crude chloride residue was suspended in toluene, sonicated and concentrated to dryness. The process was repeated three times and dried under vacuum to give the substituted methylene chloride (2), usually as an off-white solid, which was used for next step without further purification. Alternatively, a solution of aqueous 1N Na₂CO₃ is then added to produce a solution of pH˜8. the mixture was extracted with DCM (3×10-50 mL), dried over sodium sulfate, and concentrated to the crude substituted methylene chloride (2a), which is then purified by column chromatography on silica gel (0-100% ethyl acetate-hexanes).

General method D for preparing substituted methylene bromide (2b). To a solution of substituted methylene alcohol (1) (0.1 to 2 mmol) in DCM (1-10 mL) was added Ph₃P Br₂ dropwise (2 eq to 5 eq) at 0° C. or RT. The reaction mixture was stirred at RT for 10 min to 2 h, or until reaction is judged complete (LC/MS). The reaction mixture is concentrated to dryness over a rotavap. The residue purified by column chromatography on silica gel (0-100% ethyl acetate-hexanes) to afford the pure bromide 2b.

General method E (Scheme 2) for preparing heterocyclic methylene derivatives 9, 10, 12 and 13. Condensation of heterocyclic ketone analog 5 with chlorformate or dialkyl carbonate gives (hetero)cyclic beta-ketone ester 6 (Step 1). The ketone ester 6 is converted to the triflate intermediate 7 by treating with a triflating agent (e.g, triflic anhydride) in the presence of an organic base such as Hunig's base (Step 2). Suzuki coupling of the triflate 7 with a boronic acid or ester affords heterocyclohexene carboxylate 8 (Step 3). Subsequent reduction of the ester group by LAH or DIBAL gives the corresponding alcohol 9-OH (Step 4). Further reaction of the alcohol 9-OH with thionyl chloride, Ph₃PBr₂ (or CBr₄-Ph₃P or PBr₃), or alkyl/aryl sufonyl chloride produces the corresponding 10-X chloride, bromide or sulfonate (Step 3).

Alternatively, the double bond of heterocyclohexene carboxylate 8 is reduced to give the m-heterocyclohexane 11-cis carboxylate under palladium catalyzed hydrogenation conditions (Step 6). Reduction of the ester group of 11-ds by LAH or DIBAL yields cis-alcohol 12-OH-ds (Step 8). Conversion of the alcohol 12-OH-ds to its chloride, bromide or sulfonate (such as mesylate, tosylate) 13-X-cis can be achieved by reacting with thionyl chloride, or Ph₃PBr₂, or sufonyl chloride (such as mesyl chloride or tosyl chloride) (Step 9). The cis-cyclohexane carboxylate 11-ds can also be isomerized to the thermodynamically more stable trans-isomer 11-trans by the treatment with an alcoholic alkoxide (e.g., ethoxide) solution. Analogously, transformation of 11-trans ester to 12-trans alcohol and 13-X-trans halide is accomplished by applying conditions of Step 8 and Step 9 (Scheme 2) similar to these for the corresponding cis-isomers.

Coupling of the (hetero)cyclic methylene derivatives 9, 10, 12 and 13 with hydroxyl (hetero)arylaldehyde derivatives (3a/3b) (Scheme 3) by general method A or B affords the corresponding aryloxy/heteroarylether analogs (4c and 4d).

Similarly, N-linked heterocyclic analogs (compound 5, Scheme 4) can also be synthesized from animation procedures developed by Buchwald and Hartwig.

Syntheses of the ester prodrugs start with the free carboxylic acid bearing the tertiary amine. The free acid is activated for ester formation in an aprotic solvent and then reacted with a free alcohol group in the presence of an inert base, such as triethyl amine, to provide the ester prodrug. Activating conditions for the carboxylic acid include forming the acid chloride using oxalyl chloride or thionyl chloride in an aprotic solvent, optionally with a catalytic amount of dimethyl formamide, followed by evaporation. Examples of aprotic solvents, include, but are not limited to methylene chloride, tetrahydrofuran, and the like. Alternatively, activations can be performed in situ by using reagents such as BOP (benzotriazol-1-yloxytris(dimethylamino) phosphonium hexafluorolphosphate, and the like (see Nagy et al., 1993, Proc. Natl. Acad. Sci. USA 90:6373-6376) followed by reaction with the free alcohol. Isolation of the ester products can be affected by extraction with an organic solvent, such as ethyl acetate or methylene chloride, against a mildly acidic aqueous solution; followed by base treatment of the acidic aqueous phase so as to render it basic; followed by extraction with an organic solvent, for example ethyl acetate or methylene chloride; evaporation of the organic solvent layer, and recrystallization from a solvent, such as ethanol. Optionally, the solvent can be acidified with an acid, such as HCl or acetic acid to provide a pharmaceutically acceptable salt thereof. Alternatively the crude reaction can be passed over an ion exchange column bearing sulfonic acid groups in the protonated form, washed with deionized water, and eluted with aqueous ammonia; followed by evaporation.

Suitable free acids bearing the tertiary amine are commercially available, such as 2-(N-morpholino)-propionic acid, N,N-dimethyl-beta-alanine, and the like. Non-commercial acids can be synthesized in straightforward manner via standard literature procedures.

Carbonate and carbamate prodrugs can be prepared in an analogous way. For example, amino alcohols and diamines can be activated using activating agents such as phosgene or carbonyl diimidazole, to provide an activated carbonates, which in turn can react with the alcohol and/or the phenolic hydroxy group on the compounds utilized herein to provide carbonate and carbamate prodrugs.

Various protecting groups and synthetic methods related to them that can be used or adapted to make compounds of the invention can be adapted from the references Testa et al., Hydrolysis in Drug and Prodrug Metabolism, June 2003, Wiley-VCH, Zurich, 419-334 and Beaumont et al., Curr. Drug Metab. 2003, 4:461-83.

Scheme 5 below provides a method of synthesizing an acyloxymethyl version of a prodrug by adapting a method from the reference Sobolev et al., 2002, J. Org. Chem. 67:401-410.

Scheme 6 below provides a method for synthesizing a phosphonooxymethyl version of a prodrug by adapting a method from Mantyla et al., 2004, J. Med. Chem. 47:188-195.

Scheme 7 below provides a method of synthesizing an alkyloxymethyl version of a prodrug

Compounds of structure 17 can be synthesized via general synthetic scheme 8. Reduction of carboxylic acid derivative 14 gives hydroxymethyl analog, which can be N-derivativtized at via copper-mediated N-arylation reaction (CuI, Ar—I, base such as N,N-dimethylethylenediamine and potassium phosphate, heat) to give key hydroxymethyl intermediate 15. Coupling of 15 with phenol aldehyde 16 produces the desired aldehyde analog 17 via typical Mistunobu conditions using either triphenylphosphine or polymer supported triphenylphosphine.

General method step 1—reduction of carboxylic add derivative 14 to methyl alcohol 15: To a suspension of carboxylic acid 14(1-10 mmol) in MeOH or EtOH (2-10 mL) at 0° C. was added SOCl₂ (1.5 eq). After stirred at room temperature for 1-12 h, it was concentrated to remove all solvents, dried under high vacuum to give corresponding methyl or ethyl ester. The ester was dissolved in MeOH or EtOH (5-30 mL), to this solution, was added NaBH₄ (1-4 eq) at 0° C., the mixture was warmed up to room temperature and stirred for additional 1-24 h. The mixture was quenched with Sat. NH₄Cl, filtered off the insolubles and the filtrate was concentrated to give crude product, which was purified by flash silica gel chromatography to give the corresponding hydroxymethylene compound 15.

General method step 2—N-alkylation (14a to 14b): The carboxylate 14a (R₁=H) can be first alkylated and then reduced to give N-alkyl hydroxymethylene analog 14b (R₁=alkyl). In a typical procedure, the carboxylate 14a (1-10 mmol) is first dissolved in DMF (2-20 mL); to this was then added a base such as NaH or Cs₂CO₃ (1-1.2 eq), followed by the addition of alkyl halide (eg, BnBr) (0.9-1.5 eq). The reaction allowed to proceed at room temperature of heat at 40 to 115° C. for 0.5 to 24 h. In workup A, water was added to the reaction mixture, the precipitated product was collected, washed with water, and then subjected to preparative HPLC or flash silica gel chromatography purification. In workup B (for products that did not precipitate), diluted HCl or aqueous NH₄Cl was added at 0° C. to adjusted the pH to 7, the reaction mixture was partitioned between ethyl acetate or dichloromethane and aqueous sodium chloride and the organic layer separated, dried, and solvent removed under vacuum to afford crude product which was purified by automated silica gel column chromatography, reaction appropriate solvents mixture (e.g., ethyl acetate/hexanes).

General method step 3—Copper-mediated N-arylation from 15a to 15c: For cyclic amines (X=H, H), to a solution of hydroxymethylene compound 15a (1-10 mmol) and aryl/hetero iodide (1-1.5 eq) in iPrOH (0.5-10 mL) was added ethylene diol (1.3 eq) and CuI (6.7 mol %), followed by K₃PO₄ (1.3 eq), then it was degassed and heated at 88° C. for 6-24 h. Alternatively, for lactams (X═O), to a solution of hydroxymethylene compound 15a (1-10 mmol) and aryl/hetero iodide (1-1.5 eq) in Dioxane (2-20 mL) was added CuI (0.17 eq), N,N-dimethylethylenediamine (0.17 eq), K₃PO₄ (1.7 eq), then it was degassed and heated at 100° C. for 6-48 h.

Workup for both procedures: the reaction mixture was cooled to room temperature the mixture was diluted with EtOAc and water, organic layer was separated and the aqueous layer was extracted with EtOAc, organic layer was combined, washed with brine, dried and concentrated to give crude product, which was purified by flash silica gel chromatography to give N-aryl/heteroaryl compound 15c.

General method C-Mitsunobu conditions A hydroxyl (hetero)arylaldehyde derivatives (17) (0.1-2 mmol) mixture with substituted methylene alcohol (16) (0.8 to 1.2 eq) and (polymer-supported) PPh₃ (1-1.5 eq) in anhydrous THF (1-10 mL) was stirred under nitrogen until complete dissolution. The solution was cooled to 0° C. on ice bath and DIAD or DEAD (1.1 eq) in THF or toluene was added dropwise over a 1-20 min period. The ice cooling bath was allowed to expire over 90 min and the mixture was stirred at RT for 2-48 hours. The mixture was filtered through a pad of silica. The silica was washed with ethyl acetate 2-20 mL. The combined filtrates were evaporated and the residue was dried on highvac. The residue was purified by preparative HPLC or flash silica gel chromatography.

General method step 1 (Scheme 9) for preparing substituted methylene alcohol (2) by Suzuki coupling reaction. To a solution of (2-chloropyridin-3-yl)methanol or (2-bromopyridin-3-yl)methanol (1-100 mmol) and appreciate bronic acid or ester (0.8 to 1.3 eq) in dioxane (2-200 mL) was added a solution of sodium bicarbonate (3 eq) in water (1-100 mL), followed by the addition of Pd(dppf)Cl₂ (3 to 10 mol %). After heating at 100° C. for 4-24 h, the reaction mixture was cooled and diluted with EtOAc, organic layer was washed with water, brine, dried and concentrated to give crude product, which was purified by column chromatography.

General method step 2 (Scheme 9) for preparing substituted methylene chloride (3a). To a solution of substituted methylene alcohol (2) (0.1 to 2 mmol) in DCM (1-10 mL) was added SOCl₂ dropwise (2 eq to 3 eq) at 0° C. or rt. The reaction mixture was stirred at rt for 10 min to 6 h, or until reaction is judged complete (LC/MS). The reaction mixture is concentrated to dryness over a rotavap. The crude chloride residue was suspended in toluene, sonicated and concentrated to dryness. The process was repeated three times and dried under vacuum to give the substituted methylene chloride (3a), usually as an off-white solid, which was used for next step without further purification. Alternatively, a solution of aqueous 1N Na₂CO₃ is then added to produce a solution of pH˜8. the mixture was extracted with DCM (3×10-30 mL), dried over sodium sulfate, and concentrated to the crude substituted methylene chloride (3a), which is then purified by column chromatography on silica gel (0-100% ethyl acetate-hexanes).

General method 2 (Scheme 9) for preparing substituted methylene bromide (3b). To a solution of substituted methylene alcohol (2) (0.1 to 2 mmol) in DCM (1-10 mL) was added Ph₃P Br₂ dropwise (2 eq to 3 eq) at 0° C. or rt. The reaction mixture was stirred at rt for 10 min to 2 h, or until reaction is judged complete (LC/MS). The reaction mixture is concentrated to dryness over a rotavap. The residue purified by column chromatography on silica gel (0-100% ethyl acetate-hexanes) to afford the pure bromide 3b.

General method step 3 (Scheme 9) for preparing aryloxy/heteroarylether analogs (5) from substituted methylene alcohol (2) and hydroxyl (hetero)aryl aldehyde derivatives (4). A hydroxyl (hetero)arylaldehyde derivatives (4) (0.1-2 mmol) mixture with substituted methylene alcohol (2) (0.8 to 1.2 eq) and (polymer-supported)/PPh₃ (1-1.5 eq) in anhydrous THF (1-10 mL) was stirred under nitrogen until complete dissolution. The solution was cooled to 0° C. on ice bath and DIAD or DEAD (1.1 eq) in THF or toluene was added drop wise over a 1-20 min period. The ice cooling bath was allowed to expire over 90 min and the mixture was stirred at RT for 2-48 hours. The mixture was stirred for 10 min, then filtered through a pad of silica. The silica was washed with ethyl acetate 2-20 mL. The combined filtrates were evaporated and the residue was dried on highvac. The residue was purified by preparative HPLC or flash silica gel chromatography.

General method step 4 (Scheme 9) for preparing aryloxy/heteroarylether analogs (5) from substituted methylene halide (3) and hydroxyl (hetero)aryl aldehyde derivatives (4). A mixture of hydroxyl (hetero)arylaldehyde derivatives (4) (0.1-2 mmol, 1-4 eq.), substituted methylene chloride or bromide (3) (1 eq), and K₂CO₃ (2-5 eq.) (catalytic amount of NaI or Bu₄NI may also be added) in DMF, acetonitrile, NMP or DMSO (1 to 10 mL) was stirred at RT or heating up to 120° C. for 1-24 h under nitrogen atmosphere. In workup A, water was added to the reaction mixture, the precipitated product was collected, washed with water, and then subjected to preparative HPLC or flash silica gel chromatography purification. In workup B (for products that did not precipitate), diluted HCl or aqueous NR₄Cl was added at 0° C. to adjusted the pH to ˜7, the reaction mixture was partitioned between ethyl acetate or dichloromethane and aqueous sodium chloride and the organic layer separated, dried, and solvent removed under vacuum to afford crude product which was purified by automated silica gel column chromatography using appropriate solvents mixture (e.g., ethyl acetate/hexanes).

Examples

In the examples below as well as throughout the application, the following abbreviations have the following meanings. If not defined, the terms have their generally accepted meanings.

-   -   ° C.=degrees Celsius     -   RT=Room temperature     -   min=minute(s)     -   h=hour(s)     -   μL=Microliter     -   mL=Milliliter     -   mmol=Millimole     -   eq=Equivalent     -   mg=Milligram     -   ppm=Parts per million     -   atm=Atmospheric pressure     -   MS=Mass spectrometry     -   LC-MS=Liquid chromatography-mass spectrometry     -   HPLC=High performance liquid chromatography     -   NMR=Nuclear magnetic resonance     -   Sat./sat. Saturated     -   MeOH=Methanol     -   EtOH=Ethanol     -   EtOAc=Ethyl acetate     -   Et₃N=Triethylamine     -   ACN=Acetonitrile     -   AC₂O=Acetic anhydride     -   Na(OAc)₃BH=Sodium triacetoxy borohydride     -   PBr₃=phosphorus tribromide     -   Ph₃P=Triphenylphosphine     -   Ph₃PBr₂=Triphenylphosphine dibromide     -   CBr₄ Tetrabromomethane     -   DMF=N, N-Dimethylformamide     -   DCM=Dichloromethane     -   LAH/LiAlH₄=Lithium aluminum hydride     -   THF=Tetrahydrofuran     -   DIBAL=Diisobutylaluminium hydride     -   DIAD=Diisopropyl azodicarboxylate     -   DEAD=Diethyl azodicarboxylate     -   DIPEA=N,N-Diisopropylethylamine     -   Tf₂O=Trifluoromethanesulfonic (triflic) anhydride     -   Pd(dppf)Cl₂=[1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II),         complex

The following examples are given for the purpose of illustrating various embodiments of the invention and are not meant to limit the present invention in any fashion. The present examples, along with the methods described herein are presently representative of preferred embodiments, are exemplary, and are not intended as limitations on the scope of the invention. Changes therein and other uses which are encompassed within the spirit of the invention as defined by the scope of the claims will occur to those skilled in the art.

EXPERIMENTAL PROCEDURES FOR INTERMEDIATES (E)-1-(3-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-3-(dimethylamino)prop-2-en-1-one (INT-1)

Step 1

To a mixture of (2-bromopyridin-3-yl)methanol (20.0 g, 106.4 mmol, 1 eq.; refer to example 14) and imidazole (14.5 g, 212.8 mmol, 2 eq.) in DMF (50.0 mL) was added TBSCl (19.2 g, 150.7 mmol, 1.2 eq.) at RT. The mixture was stirred at RT for 1 h and diluted with a mixture of water (100 mL) and EtOAc (300 mL). The organic layer was washed with NH₄Cl_((sat.)) solution and brine, dried over Na₂SO₄, concentrated, and purified on silica gel using 10% EtOAc/hexanes as eluent to give 2-bromo-3-((tert-butyldimethylsilyloxy)methyl)pyridine (30.1 g, 94%) as a colorless oil. MS (ESI) m/z 302.0 [M+H]⁺.

Step 2

A mixture of 2-bromo-3-((tert-butyldimethylsilyloxy)methyl)pyridine (30.1 g, 100.0 mmol, 1 eq.) and Zn(CN)₂ (23.5 g, 200.0 mmol, 2.0 eq.) in DMF (100.0 mL) was purged with N₂ for 5 min and added Pd(PPh₃)₄ (5.78 g, 5.0 mmol, 0.05 eq.). The mixture was heated at 120° C. for 2 h under N₂, cooled, filtered, concentrated, and purified on silica gel using a mixture of EtOAc and hexanes as eluent to give 3-((tert-butyldimethylsilyloxy)methyl)picolinonitrile (20.4 g, 82%) as a colorless oil. MS (ESI) m/z 249.1 [M+H]⁺.

Step 3:

Methylmagnesium bromide (3M/ether, 41.0 mL, 123.4 mmol) was added to a stirred solution of 3-((tert-butyldimethylsilyloxy)methyl)picolinonitrile (20.4 g, 82.25 mmol) in THF (100.0 mL) at −78° C. The reaction mixture was warm to RT, quenched with aqueous citric acid solution, and extracted with EtOAc (50 mL) twice. The combined organic layers were washed with NaHCO_(3 (sat)) solution and brine, dried over Na₂SO₄, concentrated, and purified on silica gel using a mixture of EtOAc/hexanes as eluent to give 1-(3-((tert-butyldimethylsilyloxy)methyl)pyridin-2-yl)ethanone (12.9 g, 59%) as a colorless oil. MS (ESI) m/z 266.2 [M+H]⁺.

Step 4:

1-(3-((tert-butyldimethylsilyloxy)methyl)pyridin-2-yl)ethanone (10.8 g, 40.75 mmol) in dimethoxy-N,N-dimethylmethanamine (15.0 mL) was heated to reflux for 3 days. The mixture was concentrated and used for next step without further purification. MS (ESI) m/z 321.1 [M+H]⁺.

Preparation of 3-(chloromethyl)-2-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl)pyridine (INT-2)

Step 1:

To (3,3,3-trifluoroethyl)hydrazine (25 g, 50% wt in water, 153.5 mmol, 1 eq.) in a RB flask (250 mL) was added HCl (12 N, 25.6 mL, 307.0 mmol, 2 eq.). The mixture was concentrated to give (3,3,3-trifluoroethyl)hydrazine dihydrochloride (1.07 g) as a yellow solid. MS (ESI) m/z 115.1 [M+H]⁺.

Step 2:

To (E)-1-(3-((tert-butyldimethylsilyloxy)methyl)pyridin-2-yl)-3-(dimethylamino)prop-2-en-1-one (crude above, 5.91 g, 18.44 mmol, 1 eq.) in EtOH (20 mL) was added (3,3,3-trifluoroethyl)hydrazine dihydrochloride (4.13 g, crude above, 22.13 mmol, 1.2 eq.) at RT. The mixture was heated at 80° C. for 1 h, concentrated, and diluted with EtOAc (50 mL) and NaHCO_(3 (sat)) solution (10 mL). The layers were separated and aqueous layer was extracted with EtOAc three times. The combined organic layers were dried over Na₂SO₄, concentrated, and purified on silica gel using a mixture of EtOAc and hexanes as eluent to give 3-((tert-butyldimethylsilyloxy)methyl)-2-(1-(3,3,3-trifluoroethyl)-1H-pyrazol-5-yl)pyridine (5.90 g; 86% for 2 steps). MS (ESI) m/z 372.2 [M+H]⁺.

Step 3:

To 3-((tert-butyldimethylsilyloxy)methyl)-2-(1-(3,3,3-trifluoroethyl)-1H-pyrazol-5-yl)pyridine (5.91 g, 15.93 mmol) in MeOH (20 mL) was added HCl (4 N, 8.0 mL). The mixture was stirred at RT for 1 h, concentrated, and diluted with EtOAc (50 mL) and NaHCO_(3(sat)) solution (10 mL). The layers were separated and aqueous layer was extracted with EtOAc three times. The combined organic layers were dried over Na₂SO₄, and concentrated to give (2-(1-(3,3,3-trifluoroethyl)-1H-pyrazol-5-yl)pyridin-3-yl)methanol (4.1 g, quantitative yield) as colorless oil. ¹H NMR (400 MHz, CDCl₃) δ 8.54 (dd, J=4.7, 1.5 Hz, 1H), 7.92 (dd, J=7.9, 1.2 Hz, 1H), 7.57 (d, J=1.9 Hz, 1H), 7.30 (dd, J=7.8, 4.8 Hz, 1H), 6.50 (d, J=1.9 Hz, 1H), 5.09 (q, J=8.6 Hz, 2H), 4.63 (s, 2H), 1.76 (s, 1H). MS (ESI) m/z 258.1 [M+H]⁺.

Step 4:

To (2-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl)pyridin-3-yl)methanol (408 mg, 1.59 mmol) in DCM (5 mL) was added SOCl₂ (1.5 mL) at RT. The reaction mixture was stirred at RT for 4 h and concentrated to dryness. The crude solid was suspended in toluene and concentrated to dryness. The process was repeated three times and dried under vacuum to give 3-(chloromethyl)-2-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl)pyridine hydrochloride (498 mg) as an off-white solid, which was used for next step without further purification.

Preparation of 3-(chloromethyl)-2-(1-(3,3,3-trifluoropropyl)-1H-pyrazol-5-yl)pyridine (INT-3)

Step 1:

To a mixture of benzyl hydrazinecarboxylate (5.0 g, 30.3 mmol, 1 eq.) and DIEA (15.0 mL, 90.9 mmol, 3 eq.) in DMF (20 mL) was added 3,3,3-trifluoropropyl bromide (10.7 g 60.6 mmol, 2 eq.) at RT. The mixture was heated at 80° C. for 20 h, concentrated, and purified on silica gel using a mixture of EtOAc and hexanes as eluent to benzyl 2-(3,3,3-trifluoropropyl) hydrazinecarboxylate (4.2 g; 53%) as a white solid. ¹H NMR (400 MHz, CDCl₃) δ 7.33-7.17 (m, 5H), 6.11 (s, 1H), 5.01 (s, 2H), 4.00 (s, 1H), 3.00 (dd, J=12.2, 7.1 Hz, 2H), 2.17 (qt, J=10.8, 7.3 Hz, 2H). MS (ESI) m/z 263.1 [M+H]⁺.

Step 2:

To benzyl 2-(3,3,3-trifluoropropyl)hydrazinecarboxylate (1.7 g, 6.49 mmol, 1 eq.) in a mixture of EtOH (30 mL) were added Pd/C (1.0 g) and HCl (12 N, 2.0 mL). The mixture was charged with H₂ (60 psi), stirred at RT for 1 h, Altered, and concentrated to give (3,3,3-trifluoropropyl)hydrazine dihydrochloride (1.07 g) as a yellow solid. MS (ESI) m/z 129.1 [M+H]⁺.

Step 3:

To (E)-1-(3-((tert-butyldimethylsilyloxy)methyl)pyridin-2-yl)-3-(dimethylamino)prop-2-en-1-one (crude above, 1.73 g, 5.41 mmol, 1 eq.) in EtOH (10 mL) was added (3,3,3-trifluoropropyl)hydrazine dihydrochloride (1.30 g, crude above, 6.49 mmol, 1.2 eq.) at RT. The mixture was heated at 80° C. for 1 h, concentrated, and diluted with EtOAc (50 mL) and NaHCO_(3 (sat)) solution (10 mL). The layers were separated and aqueous layer was extracted with EtOAc three times. The combined organic layers were dried over Na₂SO₄, concentrated, and purified on silica gel using a mixture of EtOAc and hexanes as eluent to give 3-((tert-butyldimethylsilyloxy)methyl)-2-(1-(3,3,3-trifluoropropyl)-1H-pyrazol-5-yl)pyridine (1.58 g; 76% for 2 steps). ¹H NMR (400 MHz, CDCl₃) δ 8.53 (dd, J=4.7, 1.6 Hz, 1H), 7.96-7.88 (m, 1H), 7.51 (d, J=1.9 Hz, 1H), 7.29 (dd, J=7.9, 4.7 Hz, 1H), 6.34 (d, J=1.9 Hz, 1H), 4.62 (s, 2H), 4.45-4.33 (m, 2H), 2.82-2.61 (m, 2H), 0.85 (s, 8H), −0.00 (s, 5H). MS (ESI) m/z 386.2 [M+H]⁺.

Step 4:

To 3-((tert-butyldimethylsilyloxy)methyl)-2-(1-(3,3,3-trifluoropropyl)-1H-pyrazol-5-yl)pyridine (1.58 g, 4.1 mmol) in MeOH (20 mL) was added HCl (4 N, 4.0 mL). The mixture was stirred at RT for 1 h, concentrated, and diluted with EtOAc (50 mL) and NaHCO_(3(sat)) solution (10 mL). The layers were separated and aqueous layer was extracted with EtOAc three times. The combined organic layers were dried over Na₂SO₄, and concentrated to give (2-(1-(3,3,3-trifluoropropyl)-1H-pyrazol-5-yl)pyridin-3-yl)methanol (1.1 g, 99%) as colorless oil. ¹H NMR (400 MHz, CDCl₃) δ 8.64 (dd, J=4.7, 1.7 Hz, 1H), 8.00 (dd, J=7.9, 1.7 Hz, 1H), 7.57 (d, J=1.9 Hz, 1H), 7.38 (dd, J=7.9, 4.8 Hz, 1H), 6.48 (d, J=1.9 Hz, 1H), 4.69 (s, 2H), 4.51-4.43 (m, 2H), 2.85-2.72 (m, 2H), 2.70 (s, 1H). MS (ESI) m/z 272.1 [M+H]⁺.

Step 5:

To (2-(1-(2,2,2-trifluoropropyl)-1H-pyrazol-5-yl)pyridin-3-yl)methanol (140 mg, 0.52 mmol) in DCM (5 mL) was added SOCl₂ (2.0 mL) at RT. The reaction mixture was stirred at RT for 4 h and concentrated to dryness. The crude solid was suspended in toluene and concentrated to dryness. The process was repeated three times and dried under vacuum to give 3-(chloromethyl)-2-(1-(2,2,2-trifluoropropyl)-1H-pyrazol-5-yl)pyridine hydrochloride (498 mg) as an off-white solid, which was used for next step without further purification.

Preparation of 3-(chloromethyl)-2-(1-isopropyl-1H-pyrazol-5-yl)pyridine (INT-4)

Step 1: To a 500-mL flask containing the pyrazole boronate (9.0 g, 38.1 mmol), 2-chloropyridine (3.47 g, 38.1 mmol), Pd(dppf)Cl₂ ([1,1-bis(diphenylphosphino)ferrocene]dichloropalladium) (1.39 g, 1.91 mmol, 5% mol), and sodium bicarbonate (9.61 g, 114.4 mmol, 3 equiv) was added 100 mL of dioxane and 30 mL of water. The mixture was heated under nitrogen at 100° C. for 12 hrs. Then solvents were removed on a rotavap at 40° C. undervacum. The resulting brown residue was suspended in 20% EtOAc/DCM (60 mL), filtered through a pad of silica gel (15 g); washed with 20% EtOAc/DCM (4×20 mL). The combined filtrate were concentrated to afford a brown oil (13 g). The residue was dissolved 10% EtOAc/hexanes (20 mL) and loaded on a Biotage 100 g snap SiO₂ column and eluted with 0-50% EtOAc. (2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methanol was obtained as a light brown oil (3.32 g, 40%). MS (ESI) m/z 218 [M+H]⁺.

Step 2: To a solution of (2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methanol) (440 mg, 2.02 mmol) in DCM (4 mL) was added SOCl₂ (2 eq) at 0° C. The reaction mixture was stirred at RT for 15 mins and concentrated to dryness. The crude solid was suspended in toluene and concentrated to dryness. The process was repeated three times and dried under vacuum to give 3-(chloromethyl)-2-(1-isopropyl-1H-pyrazol-5-yl)pyridine hydrochloride (432 mg) as an off-white solid, which was used for next step without further purification. MS (ESI) m/z 236.5 [M+H]⁺.

Preparation of 3-(chloromethyl)-2-(1-cyclopentyl-1H-pyrazol-5-yl)pyridine (INT-5)

Step 1: To (E)-1-(3-((tert-butyldimethylsilyloxy)methyl)pyridin-2-yl)-3-(dimethylamino)prop-2-en-1-one (crude, 3.205 g, 10.0 mmol, 1 eq.) in EtOH (30 mL) was added cyclopentylhydrazine HCl salt (1.639 g, 12.0 mmol, 1.2 eq) at RT. The mixture was heated at 80° C. for 2 h, concentrated, and purified on silica gel using a mixture of EtOAc and hexanes as eluent to give a mixture of regio-isomers, the less polar (2-(1-cyclopentyl-1H-pyrazol-5-yl)pyridin-3-yl)methanol was obtained as a light brown oil (440 mg). MS (ESI) m/z 244.2 [M+H]⁺.

Step 2: To a solution of (2-(1-cyclopentyl-1H-pyrazol-5-yl)pyridin-3-yl)methanol(301 mg, 1.24 mmol) in DCM (3 mL) was added SOCl₂ (3 eq) at 0° C. The reaction mixture was stirred at RT for 15 mins (the reaction was done in 10 mins by LCMS) and concentrated to dryness. The crude solid was suspended in toluene and concentrated to dryness. The process was repeated three times and dried under vacuum to give 3-(chloromethyl)-2-(1-cyclopentyl-1H-pyrazol-5-yl)pyridine hydrochloride (305 mg) as an off-white solid, which was used for next step without further purification. MS (ESI) m/z 262.2 [M+H]⁺.

Preparation of 5-hydroxy-2-(2-methoxyethoxy)isonicotinaldehyde (INT-6)

Step 1

To a solution of 6-(benzyloxy)pyridin-3-ol (2.0 g, 10 mmol, 1 eq.) in DMF (20 mL) was added NaH (60% in mineral oil; 0.6 g, 15 mmol, 1.5 eq.) at 0-5° C. portion-wise. Upon the completion of addition, the mixture was continued to stir at 0-5° C. for 15 min, added chloromethyl methyl ether (0.88 g, 11 mmol, 1.1 eq.), stirred at 0-5° C. for another 20 min, and quenched with NH₄Cl_((sat.)) solution. The aqueous layer was extracted with EtOAc (3×20 mL) and the combined organic layers were washed with water and brine, dried over Na₂SO₄, concentrated, and purified on silica gel using 25% EtOAc/hexanes as eluent to give 2-(benzyloxy)-5-(methoxymethoxy)pyridine (2.1 g, 87%) as a colorless oil. MS (ESI) m/z 246.1 [M+H]⁺.

Step 2

To 2-(benzyloxy)-5-(methoxymethoxy)pyridine (1.8 g, 8.71 mol) in EtOH was added Pd/C (1.0 g). The mixture was charged with H₂ (15 psi), stirred at RT for 45 min, filtered, and concentrated to give 5-(methoxymethoxy)pyridin-2-ol (1.35 g, quantitative yield) as a pale yellow solid. MS (ESI) m/z 156.1 [M+H]⁺.

Step 3

To a mixture of 5-(methoxymethoxy)pyridin-2-ol (1.35 g, 8.71 mmol, 1 eq.) and K₂CO₃ (6.01 g, 43.6 mmol, 5.0 eq.) in DMF (30.0 mL) was added 1-bromo-2-methoxyethane (3.61 g, 26.1 mmol, 3 eq.). The mixture was heated at 60° C. for 2 h, cooled, filtered, concentrated, and purified on silica gel using a mixture of EtOAc and hexanes as eluent to give 2-(2-methoxyethoxy)-5-(methoxymethoxy)pyridine (500 mg, 27%) as a colorless oil. ¹H NMR (400 MHz, CDCl₃) δ 7.94 (d, J=3.0 Hz, 1H), 7.35 (ddd, J=8.9, 3.0, 1.0 Hz, 1H), 6.76 (dd, J=8.9, 1.0 Hz, 1H), 5.11 (s, 2H), 4.48-4.40 (m, 2H), 3.79-3.71 (m, 2H), 3.50 (s, 3H), 3.45 (s, 3H). MS (ESI) m/z 214.1 [M+H]⁺.

Step 4

To a mixture of 2-(2-methoxyethoxy)-5-(methoxymethoxy)pyridine (1.34 g, 6.3 mol, 1 eq.) and diisopropylamine (17.5 uL, 0.13 mmol, 0.02 eq.) in THF (50 mL) was added methyl lithium (1.6 M/THF, 7 mL, 11.3 mol, 1.8 eq.) at −40° C. Upon the completion of addition, the mixture was warmed to 0° C., continued to stir at 0° C. for 3 h, cooled back down to −40° C., and added DMF (0.83 mL, 11.3 mol, 1.8 eq.) slowly. The mixture was then stirred at −40° C. for 1 h, quenched with a mixture of HCl (12 N, 12 mL) and THF (28 mL), warmed to RT, and added water (20 mL). The pH of the mixture was adjusted to pH 8-9 with solid K₂CO₃. The aqueous layer was extracted with EtOAc (30 mL) twice. The combined organic layers were dried over Na₂SO₄, concentrated, and purified on silica gel using a mixture of EtOAc and hexanes as eluent to give a mixture of 2-(2-methoxyethoxy)-5-(methoxymethoxy)isonicotinaldehyde and 2-(2-methoxyethoxy)-5-(methoxymethoxy)nicotinaldehyde (5/1, 1.27 g, 83.6%) as a pale yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 10.45 (s, 1H), 8.23 (s, 1H), 7.16 (s, 1H), 5.27 (s, 2H), 4.46 (dd, J=5.4, 3.9 Hz, 2H), 4.14 (q, J=7.1 Hz, 1H), 3.77-3.71 (m, 2H), 3.56 (s, 3H), 3.46 (s, 3H) and ¹H NMR (400 MHz, CDCl₃) δ 10.41 (s, 1H), 8.18 (d, J=3.2 Hz, 1H), 7.85 (d, J=3.1 Hz, 1H), 5.16 (s, 2H), 4.64-4.57 (m, 2H), 3.85-3.79 (m, J=5.4, 4.0 Hz, 2H), 3.50 (s, 3H), 3.46 (s, 3H); MS (ESI) m/z 242.1 [M+H]⁺.

Step 5

To a solution of 2-methoxy-5-(methoxymethoxy)isonicotinaldehyde (1.27 g, 5.29 mol) in THF (5 mL) was added HCl (3 N, 4 mL). The reaction was stirred at 50° C. for 1 h, cooled to RT, and diluted with water (5 mL). The mixture was neutralized to pH 7-8 with solid K₂CO₃ and the aqueous layer was extracted with EtOAc (100 mL) twice. The combined organic layers were dried over Na₂SO₄, concentrated, and purified on silica gel using a mixture of EtOAc and hexanes to give 5-hydroxy-2-(2-methoxyethoxy)isonicotinaldehyde (630 mg, 60%) and 5-hydroxy-2-(2-methoxyethoxy)nicotinaldehyde (120 mg, 11%). Data for 5-hydroxy-2-(2-methoxyethoxy)isonicotinaldehyde: ¹H NMR (400 MHz, CDCl₃) δ 9.98 (s, 1H), 9.50 (s, 1H), 8.07 (s, 1H), 7.02 (s, 1H), 4.51-4.39 (m, 2H), 3.81-3.72 (m, 2H), 3.47 (s, 3H). LRMS (M+H⁺) m/z 198.1. Data for and 5-hydroxy-2-(2-methoxyethoxy) nicotinaldehyde: ¹H NMR (400 MHz, CDCl₃) δ 10.3 (s, 1H), 7.99 (d, J=3.2 Hz, 1H), 7.58 (d, J=3.2 Hz, 1H), 7.18-7.07 (br, 1H), 4.54 (dd, J=5.4, 3.7 Hz, 2H), 3.84 (dd, J=5.4, 3.7 Hz, 2H), 3.49 (s, 3H); MS (ESI) m/z 198.1 [M+H]⁺.

Preparation of 2,6-dihydroxybenzaldehyde (INT-7)

Into a 3000-mL three neck round-bottom flask, was placed a solution of AlCl₃ (240 g, 1.80 mol, 3.00 equiv) in dichloromethane (1200 mL). A solution of 2,6-dimethoxybenzaldehyde (100 g, 601.78 mmol, 1.00 equiv) in dichloromethane (800 ml) was added to the reaction mixture dropwise at 0° C. The resulting solution was stirred overnight at room temperature, and then it was quenched with 200 mL of diluted HCl (2M). The resulting solution was extracted with 2×200 mL of dichloromethane. The combined organic layers were concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:200-1:50) as eluent to furnish 40 g (48%) of 2,6-dihydroxybenzaldehyde as a yellow solid.

¹HNMR (300 MHz, DMSO-d₆) δ 11.25 (s, 2H), 10.25 (s, 1H), 7.36 (m, 1H), 6.36 (d, J=8.4 Hz 2H); MS (ESI) m/z 139 [M+H]⁺.

Preparation of 5-hydroxy-2-methoxyisonicotinaldehyde (INT-8)

Step 1: To a solution of 6-methoxypyridin-3-ol (20 g, 0.16 mol) in DMF (200 mL) was added NaH (60% in mineral oil; 9.6 g, 0.24 mol) at 0-3° C. portion-wise. Upon the completion of addition, the mixture was continued to stir at 0-3° C. for 13 min followed by additional of chloromethyl methyl ether. The mixture was stirred at 0-3° C. for another 20 min and quenched with aqueous NH₄Cl_((sat.)). The aqueous layer was extracted with EtOAc (3×100 mL) and the combined organic layer was washed with water and brine, dried over Na₂SO₄, and concentrated under reduced pressure. The residue was purified on silica gel with 23% EtOAc/hexanes as eluent to give 2-methoxy-3-(methoxymethoxy)pyridine (24.1 g, 89.3%) as a colorless oil. ¹H NMR (400 MHz; CDCl₃) 7.97 (d, 1H), 7.35 (dd, 1H), 6.70 (d, 1H), 5.12 (s, 2H), 3.91 (s, 3H), 3.51 (s, 3H); MS (ESI) m/z 170.1 [M+H]⁺.

Step 2: To a mixture of 2-methoxy-5-(methoxymethoxy)pyridine (30 g, 0.178 mol) and diisopropylamine (507 uL, 3.6 mmol) in THF (500 mL) was added methyl lithium (1.6 M/THF, 200 mL, 0.32 mol) at −40° C. Upon the completion of addition, the mixture was warmed to 0° C. and continued to stir at 0° C. for 3 h. The reaction mixture was then cooled back down to −40° C. followed by addition of DMF (24.7 mL, 0.32 mol) slowly. The mixture was then stirred at −40° C. for 1 h and quenched with a mixture of HCl (12 N, 120 mL) and THF (280 mL). Water (200 mL) was added and the pH of the mixture was adjusted to pH 8-9 with solid K₂CO₃. The mixture was extracted with EtOAc (300 mL) twice. The organic layer was combined, dried over Na₂SO₄, and concentrated to give 2-methoxy-5-(methoxymethoxy)isonicotinaldehyde (33.5 g, 95.7%) as a brown solid, which was used for next step without further purification. ¹H NMR (400 MHz; CD₃OD) 7.90 (s, 1H), 6.92 (s, 1H), 5.64 (s, 1H), 5.20 (s, 2H), 3.84 (s, 3H), 3.48 (s, 3H); MS (ESI) m/z 198.1 [M+H]⁺.

Step 3: To a solution of 2-methoxy-5-(methoxymethoxy)isonicotinaldehyde (33.5 g, 0.17 mol) in THF (150 mL) was added HCl (3 N, 250 mL). The reaction was stirred at 50° C. for 1 h, cooled to RT and diluted with water (500 mL). The mixture was neutralized to pH 7-8 with solid K₂CO₃. The pale yellow solid was collected, washed with water, and dried in vacuum oven (40° C.) overnight to give 5-hydroxy-2-methoxyisonicotinaldehyde (17.9 g, 74.6%). ¹H NMR (400 MHz; DMSO) δ=10.31 (s, 1H), 8.03 (s, 1H), 6.89 (s, 1H), 3.80 (s, 3H); MS (ESI) m/z 154.0 [M+H]⁺.

Experimental Procedures for Examples GBT527 Preparation of 2-methoxy-5-[[2-[1-(2,2,2-trifluoroethyl)pyrazol-3-yl]pyridin-3-yl]methoxy]pyridine-4-carbaldehyde

GTB527 was prepared using general method B from 5-hydroxy-2-methoxyisonicotinaldehyde and INT-2.

GBT576 Preparation of 2-oxo-5-[[2-(2-propan-2-ylpyrazol-3-yl)pyridin-3-yl]methoxy]-1H-pyridine-4-carbaldehyde

Step 1:

To (E)-1-(3-((tert-butyldimethylsilyloxy)methyl)pyridin-2-yl)-3-(dimethylamino)prop-2-en-1-one (crude, 1.03 g, 3.22 mmol, 1 eq.; INT-1) in EtOH (10 mL) was added isopropylhydrazine hydrochloride (430 mg, 3.86 mmol, 1.2 eq.). The mixture was heated at 80° C. for 2 h, cooled, added HCl (6 N, 0.3 mL), and stirred O/N. The mixture was concentrated and diluted with EtOAc (80 mL) and NaHCO_(3(sat)) (10 mL) solution. The layers were separated and the aqueous layer was extracted with EtOAc three times. The combined organic layers were dried over Na₂SO₄. concentrated, and purified on silica gel using EtOAc as eluent to give (2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methanol (500 mg, 71%) and (2-(1-isopropyl-1H-pyrazol-3-yl)pyridin-5-yl)methanol (55 mg, 25%) as pale yellow oils. Data for 2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methanol: ¹H NMR (400 MHz, CDCl₃) δ 8.67 (dd, J=4.7, 1.5 Hz, 1H), 8.0 (d, J=7.8 Hz, 1H), 7.61 (d, J=1.8 Hz, 1H), 7.39 (dd, J=7.8, 4.8 Hz, 1H), 6.37 (d, J=1.8 Hz, 1H), 4.67 (s, 2H), 4.55 (sep, J=6.6 Hz 1H), 1.98-2.05 (br, 1H), 1.47 (d, J=6.6 Hz, 6H). LRMS (M+H⁺) m/z 218.1 Data for (2-(1-isopropyl-1H-pyrazol-3-yl)pyridin-5-yl)methanol: ¹H NMR (400 MHz, CDCl₃) δ 8.62 (dd, J=4.8, 1.6 Hz, 1H), 7.72 (d, J=7.6 Hz, 1H), 7.55 (d, J=2.4 Hz, 1H), 7.23 (dd, J=7.6, 4.8 Hz, 1H), 6.99 (dd, J=8.0, 6.5 Hz, 1H), 6.07 (t, J=7.6 Hz, 1H), 4.67 (d, J=7.6 Hz, 2H), 4.58 (sep, J=6.7 Hz, 1H), 1.60 (d, J=6.7 Hz, 1H). MS (ESI) m/z 218.1 [M+H]⁺.

Step 2:

To (2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methanol (560 mg, 2.58 mmol) in DCM (10 mL) was added SOCl₂ (3.0 mL) at RT. The reaction mixture was stirred at RT for 4 h and concentrated to dryness. The crude solid was suspended in toluene and concentrated to dryness. The process was repeated three times and dried under vacuum to give 3-(chloromethyl)-2-(1-isopropyl-1H-pyrazol-5-yl)pyridine hydrochloride (700 mg) as an off-white solid, which was used for next step without further purification.

Step 3:

A mixture of 5-hydroxy-2-methoxyisonicotinaldehyde (395 mg, 2.58 mmol, 1 eq.), 3-(chloromethyl)-2-(1-isopropyl-1H-pyrazol-5-yl)pyridine hydrochloride (700 mg, 2.58 mmol, 1 eq.), and K₂CO₃ (1.4 g, 10.32 mmol, 4 eq.) in DMF (10.0 mL) was heated at 70° C. for 2 h. The mixture was cooled, filtered, concentrated, and purified on silica gel using a mixture of EtOAc and hexanes as eluent to give 5-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-2-methoxyisonicotinaldehyde (590 mg, 65%) as an off-white solid. ¹H NMR (400 MHz, CDCl₃) δ 10.41 (s, 1H), 8.76 (dd, J=4.7, 1.6 Hz, 1H), 8.04 (dd, J=7.9, 1.6 Hz, 1H), 7.90 (s, 1H), 7.61 (d, J=1.8 Hz, 1H), 7.44 (dd, J=7.9, 4.8 Hz, 1H), 7.10 (s, 1H), 6.37 (d, J=1.8 Hz, 1H), 5.14 (s, 2H), 4.65 (sep, J=6.6 Hz, 1H), 3.91 (s, 3H), 1.49 (d, J=6.6 Hz, 6H); MS (ESI) m/z 353.1 [M+H]⁺.

To 5-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-2-methoxyisonicotinaldehyde (590 mg) suspended in water (5.0 mL) was added HCl (6 N, 4 mL). Once the mixture turned into a homogeneous solution, it was freeze at −78° C. to an solid and pump under high vacuum O/N. The yellow solid was continued to pump at 45° C. for 20 h, dissolved in water (2.0 mL), and basified to pH 11 with NaOH (2 N). The aqueous layer was washed with DCM three times and the pH of the mixture was adjusted to pH 6-7. The solid was collected and dried to give 2-oxo-5-[[2-(2-propan-2-ylpyrazol-3-yl)pyridin-3-yl]methoxy]-1H-pyridine-4-carbaldehyde as a yellow solid. ¹H NMR (400 MHz, CDCl₃) δ 10.3 (s, 1H), 8.8 (dd, J=4.7, 1.6 Hz, 1H), 8.1 (dd, J=7.9, 1.5 Hz, 1H), 7.6 (s, 1H), 7.5 (d, J=1.8 Hz, 1H), 7.1 (s, 1H), 7.0 (s, 1H), 6.6 (d, J=1.8 Hz, 1H), 4.9 (s, 2H), 4.7 (sep, J=6.6 Hz, 1H), 1.5 (d, J=6.6 Hz, 6H); MS (ESI) m/z 339.4 [M+H]⁺.

GBT779 Preparation of 2-(2-morpholin-4-ylethoxy)-5-[[2-(2-propan-2-ylpyrazol-3-yl)pyridin-3-yl]methoxy]pyridine-4-carbaldehyde

GTB779 was prepared according to general method B from 5-hydroxy-2-(2-morpholinoethoxy)isonicotinaldehyde and INT-4.

¹H NMR (400 MHz, Chloroform-d) δ 10.33 (s, 1H), 8.68 (dd, J=4.8, 1.7 Hz, 1H), 7.95 (dd, J=7.9, 1.7 Hz, 1H), 7.79 (s, 1H), 7.53 (d, J=1.8 Hz, 1H), 7.36 (dd, J=7.9, 4.7 Hz, 1H), 7.04 (s, 1H), 6.28 (d, J=1.8 Hz, 1H), 5.06 (s, 2H), 4.57 (s, 0H), 4.32 (t, J=5.7 Hz, 2H), 3.69-3.62 (m, 4H), 2.70 (t, J=5.7 Hz, 2H), 2.53-2.45 (m, 4H), 1.41 (d, J=6.6 Hz, 6H); MS (ESI) m/z 452 [M+H]⁺.

GBT832 Preparation of 2-(2-methoxyethoxy)-5-[[2-[2-(2,2,2-trifluoroethyl)pyrazol-3-yl]pyridin-3-yl]methoxy]pyridine-4-carbaldehyde

GTB832 was prepared according to general method B from 5-hydroxy-2-(2-methoxyethoxy)isonicotinaldehyde (INT-5) and INT-2.

¹H NMR (400 MHz, CDCl₃) δ 10.32 (s, 1H), 8.67 (dd, J=4.8, 1.6 Hz, 1H), 7.97 (dd, J=7.9, 1.5 Hz, 1H), 7.87 (s, 1H), 7.59 (d, J=1.9 Hz, 1H), 7.38 (dd, J=7.9, 4.8 Hz, 1H), 7.11 (s, 1H), 6.47 (d, J=1.9 Hz, 1H), 5.17 (q, J=8.6 Hz, 2H), 5.10 (s, 2H), 4.39-4.32 (m, 2H), 3.70-3.63 (m, 2H); MS (ESI) m/z 437 [M+H]⁺.

GBT835 Preparation of 6-methyl-3-[[2-[2-(2,2,2-trifluoroethyl)pyrazol-3-yl]pyridin-3-yl]methoxy]pyridine-2-carbaldehyde

GTB835 was prepared according to general method B from 3-hydroxy-6-methylpicolinaldehyde and INT-2.

¹H NMR (400 MHz, CDCl₃) δ 10.23 (s, 1H), 8.64 (dd, J=4.7, 1.6 Hz, 1H), 8.16 (dd, J=7.9, 1.5 Hz, 1H), 7.61 (d, J=1.9 Hz, 1H), 7.38 (dd, J=7.9, 4.8 Hz, 1H), 7.21 (d, J=8.6 Hz, 1H), 7.10 (d, J=8.6 Hz, 1H), 6.47 (d, J=1.9 Hz, 1H), 5.19 (q, J=8.6 Hz, 2H), 5.12 (d, J=6.1 Hz, 2H), 2.51 (s, 3H); MS (ESI) m/z 377 [M+H]⁺.

GBT836 Preparation of 6-methyl-3-[[2-[2-(3,3,3-trifluoropropyl)pyrazol-3-yl]pyridin-3-yl]methoxy]pyridine-2-carbaldehyde

GTB836 was prepared according to general method B from 3-hydroxy-6-methylpicolinaldehyde and INT-3.

¹H NMR (400 MHz, CDCl₃) δ 10.31 (s, 1H), 8.75 (dd, J=4.7, 1.7 Hz, 1H), 8.27 (dd, J=7.9, 1.6 Hz, 1H), 7.62 (d, J=1.9 Hz, 1H), 7.49 (dd, J=7.9, 4.8 Hz, 1H), 7.33 (d, J=8.6 Hz, 1H), 7.24 (d, J=8.6 Hz, 1H), 6.46 (d, J=1.9 Hz, 1H), 5.18 (s, 2H), 4.61-4.44 (m, 2H), 2.96-2.75 (m, 2H), 2.62 (s, 3H); MS (ESI) m/z 391 [M+H]⁺.

GBT839 Preparation of 3-[[2-[2-(2,2,2-trifluoroethyl)pyrazol-3-yl]pyridin-3-yl]methoxy]pyridine-2-carbaldehyde

GTB839 was prepared according to general method B from 3-hydroxypicolinaldehyde and INT-2.

¹H NMR (400 MHz, CDCl₃) δ 10.26 (s, 1H), 8.65 (dd, J=4.7, 1.5 Hz, 1H), 8.38 (dd, J=4.4, 1.0 Hz, 1H), 8.19 (dd, J=7.9, 1.0 Hz, 1H), 7.61 (d, J=1.9 Hz, 1H), 7.43-7.33 (m, 2H), 7.21 (d, J=8.6 Hz, 1H), 6.48 (d, J=1.9 Hz, 1H), 5.19 (q, J=8.6 Hz, 2H), 5.15 (s, 2H); MS (ESI) m/z 363.1 [M+H]⁺.

GBT840 Preparation of 3-[[2-[2-(3,3,3-trifluoropropyl)pyrazol-3-yl]pyridin-3-yl]methoxy]pyridine-2-carbaldehyde

GTB839 was prepared according to general method B from 3-hydroxypicolinaldehyde and INT-3.

¹H NMR (400 MHz, CDCl₃) δ 10.24 (s, 1H), 8.66 (dd, J=4.7, 1.6 Hz, 1H), 8.39 (dd, J=4.5, 1.1 Hz, 1H), 8.21 (dd, J=7.9, 1.6 Hz, 1H), 7.53 (d, J=1.9 Hz, 1H), 7.44-7.37 (m, 2H), 7.26 (d, J=8.5 Hz, 1H), 6.37 (d, J=1.9 Hz, 1H), 5.13 (s, 2H), 4.49-4.40 (m, 2H), 2.87-2.64 (m, 2H); MS (ESI) m/z 377.1 [M+H]⁺.

GBT841 Preparation of 3-chloro-5-[[2-(2-propan-2-ylpyrazol-3-yl)pyridin-3-yl]methoxy]pyridine-4-carbaldehyde

GTB841 was prepared according to general method B from 3-chloro-5-hydroxyisonicotinaldehyde and INT-4.

¹H NMR (400 MHz, CDCl₃) δ 10.51 (s, 1H), 8.77 (dd, J=4.7, 1.6 Hz, 1H), 8.41 (s, 1H), 8.28 (s, 1H), 8.13 (dd, J=7.9, 1.5 Hz, 1H), 7.63 (d, J=1.8 Hz, 1H), 7.47 (dd, J=7.9, 4.8 Hz, 1H), 6.37 (d, J=1.8 Hz, 1H), 5.23 (s, 2H), 4.66 (sep, J=6.6 Hz, 1H), 1.49 (d, J=6.6 Hz, 6H); MS (ESI) m/z 357 [M+H]⁺.

GBT844 Preparation of 3-chloro-5-[[2-[2-(2,2,2-trifluoroethyl)pyrazol-3-yl]pyridin-3-yl]methoxy]pyridine-4-carbaldehyde

GTB844 was prepared according to general method B from 3-chloro-5-hydroxyisonicotinaldehyde and INT-2.

¹H NMR (400 MHz, CDCl₃) δ 10.43 (s, 1H), 8.67 (dd, J=4.7, 1.5 Hz, 1H), 8.35 (s, 1H), 8.26 (s, 1H), 8.06 (dd, J=7.9, 1.3 Hz, 1H), 7.61 (d, J=1.9 Hz, 1H), 7.40 (dd, J=7.9, 4.8 Hz, 1H), 6.47 (d, J=1.9 Hz, 1H), 5.21-5.10 (m, 4H); MS (ESI) m/z 397 [M+H]⁺.

GBT860 Preparation of tert-butyl 4-(((4-formyl-6-methoxypyridin-3-yl)oxy)methyl)-5-(1-isopropyl-1H-pyrazol-5-yl)-3,6-dihydropyridine-1 (2H)-carboxylate

Step 1: To a solution of 1-tert-butyl 4-ethyl 3-oxopiperidine-1,4-dicarboxylate (2.0 g, 7.37 mmol) in DCM (45 mL) was added DIPEA (1.54 ml, 8.84 mmol) and Tf₂O (1.36 mL, 8.11 mmol) at −78° C., then the temperature was warmed up to room temperature and the solution was stirred at RT for 1.5 h, the mixture was diluted with DCM (100 mL), organic layer was washed with Sat. NaHCO₃, brine, dried and concentrated to give 1-(tert-butyl) 4-ethyl 5-(((trifluoromethyl)sulfonyl)oxy)-3,6-dihydropyridine-1,4(2H)-dicarboxylate, which was used for next step without purification.

Step 2: To a solution of 1-tert-butyl 4-ethyl 3-(((trifluoromethyl)sulfonyl)oxy)-5,6-dihydropyridine-1,4(2H)-dicarboxylate (1.49 g, 3.7 mmol) and (1-isopropyl-1H-pyrazol-5-yl)boronic acid (0.37 g, 3.7 mmol) in dioxane (10 mL) was added Pd(dppf)Cl₂ (0.27 g, 0.37 mmol) and a solution of sodium carbonate (1.18 g, 11.10) in water (3 ml), the mixture was degased with N₂ for 3 min, and was heated at 100° C. for 13 h, after cooling to room temperature the mixture was diluted with EtOAc and washed with Sat. NaHCO₃ and brine, organic layer was combined, dried and concentrated to give crude product, which was purified by column chromatography (Hexanes/EtOAc=3:1) to give desired product 830 mg (62%).

Step 3: To a solution of 1-(tert-butyl) 4-ethyl 5-(1-isopropyl-1H-pyrazol-5-yl)-3,6-dihydropyridine-1,4(2H)-dicarboxylate (430 mg, 1.24 mmol) in THF (6 mL) was added LiAlH₄ (1M in THF, 1.49 mL, 1.49 mmol) at −20° C., the reaction was stirred at −20° C. for 30 min, and was quenched with Sat. NH₄Cl, the aqueous layer was extracted with EtOAc, the combined organics were washed with brine, dried and concentrated to give crude oil, which was purified by column (Hexanes/EtOAc=100:0 to 40:60) to give tert-butyl 4-(hydroxymethyl)-5-(1-isopropyl-1H-pyrazol-5-yl)-3,6-dihydropyridine-1 (2H)-carboxy late (370 mg, 91%).

Step 4: To a solution of give tert-butyl 4-(hydroxymethyl)-3-(1-isopropyl-1H-pyrazol-5-yl)-3,6-dihydropyridine-1(2H)-carboxylate (25 mg, 0.08 mmol) in DCM (1 mL) was added triphenylphosphine bromine adduct (40 mg, 0.09 mmol) at room temperature, after stirring for 30 min, it was diluted with DCM, washed with Sat. NaHCO3, brine, dried and concentrated to give crude product, which was purified by column to give tert-butyl 4-(bromomethyl)-5-(1-isopropyl-1H-pyrazol-5-yl)-3,6-dihydropyridine-1 (2H)-carboxy late (18 mg).

Step 5: To a solution of tert-butyl 4-(bromomethyl)-5-(1-isopropyl-1H-pyrazol-5-yl)-3,6-dihydropyridine-1(2H)-carboxylate (18 mg, 0.05 mmol) and 5-hydroxy-2-methoxyisonicotinaldehyde (10 mg, 0.06 mmol) in DMF (1 mL) was added K₂CO₃ (14 mg, 0.1 mmol). After stirred at room temperature for 1 h, it was diluted with water and EtOAc, organic layer was separated, and the aqueous layer was extracted with EtOAc, organic layer was combined, washed with brine, dried and concentrated to give crude product, which was purified by column (Hexanes/EtOAc=2:1) to give tert-butyl 4-(((4-formyl-6-methoxypyridin-3-yl)oxy)methyl)-3-(1-isopropyl-1H-pyrazol-5-yl)-5,6-dihydropyridine-1 (2H)-carboxy late (7.2 mg). 1H NMR (400 MHz, CDCl₃) (ppm) 10.39 (s, 1H), 7.79 (s, 1H), 7.56 (d, J=1.6 Hz, 1H), 7.05 (s, 1H), 6.11 (d, J=1.6 Hz, 1H), 4.40 (s, 2H), 4.38 (m, 1H), 4.01 (s, 2H), 3.88 (s, 3H), 3.66 (bs, 2H), 2.46 (bs, 2H), 1.48 (s, 9H), 1.43 (d, 6.4 Hz, 6H). MS (ESI) m/z 457.3 [M+H]⁺.

GBT861 Preparation of 2-hydroxy-6-((5-(1-isopropyl-1H-pyrazol-5-yl)-3,6-dihydro-2H-pyran-4-yl)methoxy)benzaldehyde

Step 1: To a solution of ethyl 3-oxotetrahydro-2H-pyran-4-carboxylate (1.0 g, 5.81 mmol) in DCM (30 mL) was added DIPEA (1.22 mL, 6.97 mmol) and Tf2O (1.08 mL, 6.39 mmol) at −78° C., then it was warmed up to room temperature and stirred at room temperature for 2 h, the solution was diluted with DCM, washed with Sat. NaHCO3, brine, dried and concentrated to give ethyl 5-(((trifluoromethyl)sulfonyl)oxy)-3,6-dihydro-2H-pyran-4-carboxylate as crude product (2 g).

Step 2: To a solution of ethyl 5-(((trifluoromethyl)sulfonyl)oxy)-3,6-dihydro-2H-pyran-4-carboxylate (crude from step 1) and 1-isopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.37 g, 3.82 mmol) in dioxane (20 ml) was added Pd(dppf)Cl₂ (430 mg, 0.58 mmol) and Na₂CO₃ (1.85 g, 17.46 mmol) in water (6 mL), the mixture was degased with N2 for 5 min, and was heated at 100° C. for 15 h, after cooling to room temperature the mixture was diluted with EtOAc and washed with Sat. NaHCO₃ and brine, organic layer was combined, dried and concentrated to give crude product, which was purified by column chromatography (Hexanes/EtOAc=3:1) to give ethyl 5-(1-isopropyl-1H-pyrazol-5-yl)-3,6-dihydro-2H-pyran-4-carboxylate (850 mg).

Step 3: To a solution of ethyl 5-(1-isopropyl-1H-pyrazol-5-yl)-3,6-dihydro-2H-pyran-4-carboxylate (600 mg, 2.27 mmol) in THF (10 mL) was added LiAlH₄ (1M in THF, 2.72 mL, 2.72 mmol) at −20° C., the reaction was stirred at −20° C. for 30 min, and was quenched with Sat. NH₄Cl, the aqueous layer was extracted with EtOAc, the combined organics were washed with brine, dried and concentrated to give crude oil, which was purified by column (Hexanes/EtOAc=100:0 to 20:80) to give (5-(1-isopropyl-1H-pyrazol-5-yl)-3,6-dihydro-2H-pyran-4-yl)methanol (500 mg).

Step 4: To a solution of (5-(1-isopropyl-1H-pyrazol-5-yl)-3,6-dihydro-2H-pyran-4-yl)methanol (300 mg, 1.33 mmol) in DCM (3 mL) was added dibromotriphenylphosphorane (630 mg, 1.33 mmol) at room temperature, after stirring for 30 min, it was diluted with DCM, organic layer was washed with Sat. NaHCO₃, brine, dried and concentrated to give crude product, which was purified by column(Hexanes/EtOAc=4:1) to give 5-(4-(bromomethyl)-5,6-dihydro-2H-pyran-3-yl)-1-isopropyl-1H-pyrazole (360 mg).

Step 5: To a solution of 5-(4-(bromomethyl)-5,6-dihydro-2H-pyran-3-yl)-1-isopropyl-1H-pyrazole (110 mg, 0.38 mmol) and 2,6-dihydroxybenzaldehyde (100 mg, 0.76 mmol) in DMF (6 mL) was added K₂CO₃ (110 mg, 0.76 mmol). After stirred at room temperature for 1 h, it was diluted with water and EtOAc, organic layer was separated, and the aqueous layer was extracted with EtOAc. Organic layer was combined, washed with brine, dried and concentrated to give crude product, which was purified by column (Hexanes/EtOAc=1:1) to give 2-hydroxy-6-((5-(1-isopropyl-1H-pyrazol-5-yl)-3,6-dihydro-2H-pyran-4-yl)methoxy)benzaldehyde (90 mg). 1H NMR (400 MHz, CDCl₃) δ (ppm) 11.89 (s, 1H), 10.33 (s, 1H), 7.53 (d, J=1.6 Hz, 1H), 7.33 (t, J=8.8 Hz, 1H), 6.51 (d, J=8.8 Hz, 1H), 6.16 (d, J=8.0 Hz, 1H), 6.08 (d, J=2.0 Hz, 1H), 4.40 (dd, J=12.8, 6.4 Hz, 1H), 4.35 (s, 2H), 4.18 (s, 2H), 3.97 (t, J=5.2 Hz, 2H), 2.44 (s, 2H), 1.40 (d, J=6.4 Hz, 6H); MS (ESI) m/z 343.3 [M+H]⁺.

GBT863 Preparation of 2-methoxy-5-[[5-(2-propan-2-ylpyrazol-3-yl)-3,6-dihydro-2H-pyran-4-yl]methoxy]pyridine-4-carbaldehyde

To a solution of 5-(4-(bromomethyl)-5,6-dihydro-2H-pyran-3-yl)-1-isopropyl-1H-pyrazole (50 mg, 0.19 mmol) (see the synthesis of GBT861) and 5-hydroxy-2-methoxyisonicotinaldehyde (30 mg, 0.23 mmol) in DMF (1 mL) was added K₂CO₃ (50 mg, 0.38 mmol). After stirred at room temperature for 3 h, it was diluted with water and EtOAc, organic layer was separated, and the aqueous layer was extracted with EtOAc, organic layer was combined, washed with brine, dried and concentrated to give crude product, which was purified by column (Hexanes/EtOAc=1:1) to give 5-((5-(1-isopropyl-1H-pyrazol-5-yl)-3,6-dihydro-2H-pyran-4-yl)methoxy)-2-methoxyisonicotinaldehyde (26 mg). 1H NMR (400 MHz, CDCl₃) δ (ppm) 10.40 (s, 1H), 7.81 (s, 1H), 7.54 (d, J=1.6 Hz, 1H), 7.05 (s, 1H), 6.08 (d, J=1.6 Hz, 1H), 4.42 (s, 2H), 4.40 (m, 1H), 4.19 (s, 2H), 3.98 (t, J=5.6 Hz, 2H), 3.88 (s, 3H), 2.47 (s, 2H), 1.41 (d, J=6.8 Hz, 6H); MS (ESI) m/z 358.4 [M+H]⁺.

GBT864 Preparation of 6-methyl-3-[[5-(2-propan-2-ylpyrazol-3-yl)-3,6-dihydro-2H-pyran-4-yl]methoxy]pyridine-2-carbaldehyde

To a solution of 5-(4-(bromomethyl)-5,6-dihydro-2H-pyran-3-yl)-1-isopropyl-1H-pyrazole (30 mg, 0.19 mmol) (see the synthesis of GBT861) and 3-hydroxy-6-methylpicolinaldehyde (30 mg, 0.24 mmol) in DMF (1 mL) was added K₂CO₃ (30 mg, 0.38 mmol). After stirred at room temperature for 3 h, it was diluted with water and EtOAc, organic layer was separated, and the aqueous layer was extracted with EtOAc, organic layer was combined, washed with brine, dried and concentrated to give crude product, which was purified by column (Hexanes/EtOAc=40:60) to give 5-((5-(1-isopropyl-1H-pyrazol-5-yl)-3,6-dihydro-2H-pyran-4-yl)methoxy)-2-methoxyisonicotinaldehyde (37 mg). 1H NMR (400 MHz, CDCl₃) δ (ppm) 10.30 (s, 1H), 7.54 (d, J=1.6 Hz, 1H), 7.24 (d, J=8.4 Hz, 1H), 7.09 (d, J=9.2 Hz, 1H), 6.08 (d, J=2.0 Hz, 1H), 4.42 (m, 1H), 4.38 (s, 2H), 4.18 (s, 2H), 3.98 (t, J=5.6 Hz, 2H), 2.56 (s, 3H), 2.51 (s, 2H), 1.39 (d, J=6.4 Hz, 6H); MS (ESI) m/z 342.4 [M+H]⁺.

GBT867 Preparation of 2-hydroxy-6-[(5-phenyl-3,6-dihydro-2H-pyran-4-yl)methoxy]benzaldehyde

Step 1: To a solution of ethyl 5-(((trifluoromethyl)sulfonyl)oxy)-3,6-dihydro-2H-pyran-4-carboxylate (1.77 g, 5.81 mmol) and phenylboronic acid (1.42 g, 11.62 mmol) in dioxane (15 ml) was added Pd(dppf)Cl₂ (430 mg, 0.58 mmol) and Na₂CO₃ (1.85 g, 17.46 mmol) in water (4.5 mL), the mixture was degased with N2 for 5 min, and was heated at 100° C. for 15 h, after cooling to room temperature the mixture was diluted with EtOAc and washed with Sat. NaHCO₃ and brine, organic layer was combined, dried and concentrated to give crude product, which was purified by column chromatography (Hexanes/EtOAc=4:1) to give ethyl 5-phenyl-3,6-dihydro-2H-pyran-4-carboxylate (1.05 g, 78%).

Step 2: To a solution of ethyl 5-phenyl-3,6-dihydro-2H-pyran-4-carboxylate (1.05 g, 4.52 mmol) in THF (20 mL) was added LiAlH₄ (1M in THF, 5.42 mL, 5.42 mmol) at −20° C., the reaction was stirred at −20° C. for 30 min, and was quenched with Sat. NH₄Cl, the aqueous layer was extracted with EtOAc, the combined organics were washed with brine, dried and concentrated to give crude oil, which was purified by column (Hexanes/EtOAc=100:0 to 35:65) to give (5-phenyl-3,6-dihydro-2H-pyran-4-yl)methanol (720 mg).

Step 3: To a solution of (5-phenyl-3,6-dihydro-2H-pyran-4-yl)methanol (360 mg, 1.89 mmol) in DCM (6 mL) was added dibromotriphenylphosphorane (880 mg, 2.08 mmol) at room temperature, after stirring for 30 min, it was diluted with DCM, organic layer was washed with Sat. NaHCO3, brine, dried and concentrated to give crude product, which was purified by column(Hexanes/EtOAc=9:1) to give 4-(bromomethyl)-5-phenyl-3,6-dihydro-2H-pyran (380 mg).

Step 4: To a solution of 4-(bromomethyl)-S-phenyl-3,6-dihydro-2H-pyran (110 mg, 0.45 mmol) and 2,6-dihydroxybenzaldehyde (120 mg, 0.90 mmol) in DMF (3 mL) was added K₂CO₃ (120 mg, 0.90 mmol). After stirred at room temperature for 1 h, it was diluted with water and EtOAc, organic layer was separated, and the aqueous layer was extracted with EtOAc. Organic layer was combined, washed with brine, dried and concentrated to give crude product, which was purified by column (Hexanes/EtOAc=3:1) to give 2-hydroxy-6-((5-phenyl-3,6-dihydro-2H-pyran-4-yl)methoxy)benzaldehyde (120 mg). 1H NMR (400 MHz, CDCl₃) δ (ppm) 11.92 (s, 1H), 10.36 (s, 1H), 7.35 (m, 4H), 7.18 (m, 2H), 6.49 (d, J=8.0 Hz, 1H), 6.13 (d, J=8.0 Hz, 1H), 4.48 (s, 2H), 4.32 (s, 2H), 3.95 (t, J=5.6 Hz, 2H), 2.41 (m, 2H); MS (ESI) m/z 309.

GBT868 Preparation of 3-methoxy-5-[[2-[2-(2,2,2-trifluoroethyl)pyrazol-3-yl]pyridin-3-yl]methoxy]pyridine-4-carbaldehyde

To a solution of 3-hydroxy-5-methoxyisonicotinaldehyde (0.13 g, 0.88 mmol) in DMF was added 3-(chloromethyl)-2-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl)pyridine (0.24 g, 0.88 mmol) (INT-2) and potassium carbonate (0.49 g, 3.52 mmol) and the reaction mixture was heated (60° C.). After 3 hours, the reaction mixture was filtered through a plug of silica (MeOH/CH₂Cl₂, 0-20%). Purification of the resulting residue by Prep-HPLC, provided 2-methoxy-6-((2-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde (12 mg, 5% yield). ¹H NMR (400 MHz, Chloroform-d) δ 10.54 (s, 1H), 8.71 (dd, J=5.0, 1.8 Hz, 1H), 8.23 (s, 1H), 8.21 (ddd, J=7.9, 1.7, 0.7 Hz, 1H), 8.10 (s, 1H), 7.67 (dd, J=1.9, 0.5 Hz, 1H), 7.46 (dd, J=8.0, 4.5 Hz, 1H), 7.26 (d, J=0.5 Hz, 3H), 6.56 (dd, J=1.9, 0.5 Hz, 1H), 5.23 (s, 2H), 5.28-5.15 (m, 2H), 4.04 (s, 3H); MS (ESI) m/z 393 [M+H]⁺.

GBT870 Preparation of 2-methoxy-5-[[2-(2-methoxyphenyl)pyridin-3-yl]methoxy]pyridine-4-carbaldehyde

Step 1: Into a 50-mL round-bottom flask, was placed a solution of (2-chloropyridin-3-yl)methanol (500 mg, 3.48 mmol, 1.00 equiv) in a solvent mixture of dioxane and H₂O (10/10 mL). (2-Methoxyphenyl)boronic acid (532 mg, 3.50 mmol, 1.20 equiv), sodium bicarbonate (882 mg, 10.50 mmol, 3.00 equiv), and Pd(dppf)Cl₂ (286 mg, 0.39 mmol, 0.10 equiv) were added to the reaction mixture. The resulting solution was stirred for 2 h at 100° C., and then it was diluted with 100 mL of H₂O. The resulting solution was extracted with 2×100 mL of ethyl acetate, and the combined organic layers were concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:5) as eluent to furnish 650 mg (87%) of [2-(2-methoxyphenyl)pyridin-3-yl]methanol as a yellow solid.

Step 2: Into a 50-mL round-bottom flask, was placed a solution of [2-(2-methoxyphenyl)pyridin-3-yl]methanol (600 mg, 2.79 mmol, 1.00 equiv) in thionyl chloride (10 mL). The resulting solution was heated to reflux for 2 hr, and then it was concentrated under vacuum. This resulted in 600 mg (92%) of 3-(chloromethyl)-2-(2-methoxyphenyl)pyridine as a yellow solid.

Step 3: Into a 100-mL round-bottom flask, was placed a solution of 3-(chloromethyl)-2-(2-methoxyphenyl)pyridine (306 mg, 1.31 mmol, 1.00 equiv) in CH₃CN (20 mL). 5-Hydroxy-2-methoxypyridine-4-carbaldehyde (200 mg, 1.31 mmol, 1.00 equiv), potassium carbonate (364 mg, 2.63 mmol, 2.00 equiv), and KI (44 mg, 0.27 mmol, 0.20 equiv) were added to the reaction mixture. The resulting solution was stirred for 5 h at 60° C., and then it was concentrated under vacuum. The crude product (200 mg) was purified by Prep-HPLC with the following conditions (Prep-HPLC-010): Column, SunFire Prep C18 OBD Column, 5 um, 19*150 mm; mobile phase, water with 0.1% HCOOH and MeCN (10.0% MeCN up to 40.0% in 10 min, up to 95.0% in 2 min, down to 10.0% in 2 min); Detector, Waters2545 UvDector 254&220 nm. This resulted in 65 mg (9%) of 2-methoxy-5-[[2-(2-methoxyphenyl)pyridin-3-yl]methoxy]pyridine-4-carbaldehyde bis(trifluoroacetic acid) as a yellow solid. The compound exhibited a melting point of 105-107° C. ¹HNMR (300 MHz, CDCl₃) δ 10.32 (s, 1H), 8.69 (s, 1H), 7.93 (m, 2H), 7.36 (m, 3H), 6.99 (m, 3H), 5.35 (s, 2H), 3.86 (m, 6H); MS (ESI) m/z 351 [M+H]⁺.

GBT871 Preparation of 2-methoxy-5-[[2-(3-methoxyphenyl)pyridin-3-yl]methoxy]pyridine-4-carbaldehyde

Step 1: Into a 50-mL round-bottom flask, which was purged and maintained with an inert atmosphere of nitrogen, was placed a solution of (3-methoxyphenyl)boronic acid (1.6 g, 10.53 mmol, 1.20 equiv), (2-chloropyridin-3-yl)methanol (1 g, 6.97 mmol, 1.00 equiv), sodium bicarbonate (1.7 g, 20.24 mmol, 3.00 equiv), Pd(dppf)Cl₂ (0.57 g, 0.10 equiv) in a solvent mixture of dioxane (10 mL) and water (10 mL). The resulting solution was stirred for 1.5 h at 100° C., and then it was diluted with 20 mL of H₂O. The resulting solution was extracted with 2×50 mL of ethyl acetate, and the combined organic layers were concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:50-1:1) as eluent to yield 1.3 g (87%) of [2-(3-methoxyphenyl)pyridin-3-yl]methanol as a colorless oil.

Step 2: Into a 50-mL round-bottom flask, was placed a solution of [2-(3-methoxyphenyl)pyridin-3-yl]methanol (1 g, 4.65 mmol, 1.00 equiv) in thionyl chloride (20 mL). The resulting solution was stirred for 2 h at reflux. The resulting mixture was concentrated under vacuum to furnish 600 mg (55%) of 3-(chloromethyl)-2-(3-methoxyphenyl)pyridine as a white solid.

Step 3: Into a 100-mL round-bottom flask, was placed a solution of 3-(chloromethyl)-2-(3-methoxyphenyl)pyridine (234 mg, 1.00 mmol, 1.00 equiv), 5-hydroxy-2-methoxypyridine-4-carbaldehyde (153 mg, 1.00 mmol, 1.00 equiv), and potassium carbonate (278 mg, 2.01 mmol, 2.00 equiv) in CH₃CN (30 mL). The resulting solution was stirred for 4 h at 70° C., and then it was concentrated under vacuum. The crude product (200 mg) was purified by Prep-HPLC with the following conditions (Prep-HPLC-010): Column, SunFire Prep C18 OBD Column, 5 um, 19*150 mm; mobile phase, water with 0.1% TFA and MeCN (20% MeCN up to 40% in 10 min, up to 95% in 2 min, down to 20% in 1 min); Detector, Waters2545 UvDector 254&220 nm. This resulted in 100.8 mg (17%) of 2-methoxy-5-[[2-(3-methoxyphenyl)pyridin-3-yl]methoxy]pyridine-4-carbaldehyde bis(trifluoroacetic acid) as a yellow solid.

¹HNMR (300 MHz, DMSO-d₆) δ 10.01 (s, 1H), 8.65 (m, 1H), 8.39 (s, 1H), 8.10 (m, 2H), 7.57 (d, J=9 Hz, 2H), 7.42 (m, 1H), 6.97 (m, 3H), 5.33 (s, 2H) 3.80 (m, 6H); MS (ESI) m/z 351 [M+H]⁺.

GBT874 Preparation of 2-hydroxy-6-[(1-methyl-5-phenyl-3,6-dihydro-2H-pyridin-4-yl)methoxy]benzaldehyde

Step 1: To a solid of tert-butyl 4-(hydroxymethyl)-3-phenyl-5,6-dihydropyridine-1(2H)-carboxylate (300 mg, 1.04 mmol) in round bottom flask was added 4N HCl in dioxane (6 mL) at room temperature, after stirring for 1 h, the mixture was concentrated and dried under high vacuum to give (5-phenyl-1,2,3,6-tetrahydropyridin-4-yl)methanol as HCl salt.

Step 2: To a solution of (5-phenyl-1,2,3,6-tetrahydropyridin-4-yl)methanol hydrochloride (230 mg, 1.04 mmol) in ACN (10 mL) was added Et₃N (0.15 mL, 1.04 mmol) followed by formalin (340 mg, 4.16 mmol). After stirred at room temperature for 10 min, it was added Na(OAc)₃BH (440 mg, 2.08 mmol) and was stirred for 30 min, the mixture was concentrated to remove most of the ACN, and the residue was diluted with CHCl₃, organic layer was washed with Sat. NaHCO₃, brine, dried and concentrated to give crude product, which was purified by column (DCM/MeOH=9:1) to give (1-methyl-5-phenyl-1,2,3,6-tetrahydropyridin-4-yl)methanol (140 mg).

Step 3: To a solution of (1-methyl-5-phenyl-1,2,3,6-tetrahydropyridin-4-yl)methanol (130 mg, 0.64 mmol) in DCM (4 mL) was added SOCl₂ (1.16 mL, 16 mmol) at room temperature, after stirred at room temperature for 30 min, the mixture was concentrated, dried under high vacuum to give 4-(chloromethyl)-1-methyl-5-phenyl-1,2,3,6-tetrahydropyridine as crude HCl salt.

Step 4: To a suspension of K₂CO₃ (350 mg, 2.56 mmol) and 2,6-dihydroxybenzaldehyde (180 mg, 1.28 mmol) in DMF (3 ml) was added a solution of 4-(chloromethyl)-1-methyl-5-phenyl-1,2,3,6-tetrahydropyridine (140 mg, 0.64 mmol) in DMF (4 mL), the mixture was heated at 50° C. for 3 h, cooled to room temperature, and was diluted with EtOAc, organic layer was separated and aqueous layer was extracted with EtOAc. EtOAc layers were combined, washed with Sat. NaHCO₃, brine, dried over Na₂SO₄, and was concentrated to give crude oil, which was purified by column (Hexane/EtOAc=1:1 followed by DCM/MeOH=90:10) to give 2-hydroxy-6-((1-methyl-5-phenyl-1,2,3,6-tetrahydropyridin-4-yl)methoxy)benzaldehyde (55 mg). 1H NMR (400 MHz, CDCl₃) δ (ppm) 11.92 (s, 1H), 10.35 (s, 1H), 7.34 (m, 5H), 7.19 (dd, J=8.4, 8.0 Hz, 1H), 6.46 (d, J=8.4 Hz, 1H), 6.16 (d, J=8.0 Hz, 1H), 4.45 (s, 2H), 3.20 (s, 2H), 2.68 (t, J=5.6 Hz, 2H), 2.47 (m, 2H), 2.42 (s, 3H); MS (ESI) m/z 324.3 [M+H]⁺.

GBT875 Preparation of 2-methoxy-5-[[2-(4-methoxyphenyl)pyridin-3-yl]methoxy]pyridine-4-carbaldehyde

Step 1: Into a 50-mL round-bottom flask, which was purged and maintained with an inert atmosphere of nitrogen, was placed a solution of (4-methoxyphenyl)boronic acid (1.6 g, 10.53 mmol, 1.20 equiv), (2-chloropyridin-3-yl)methanol (1 g, 6.97 mmol, 1.00 equiv), sodium bicarbonate (1.7 g, 20.24 mmol, 3.00 equiv), Pd(dppf)Cl₂ (0.57 g, 0.10 equiv) in a solvent mixture of dioxane (10 mL) and water (10 mL). The resulting solution was stirred for 1.5 h at 100° C., and then it was diluted with 20 mL of H₂O. The resulting solution was extracted with 2×50 mL of ethyl acetate, and the combined organic layers were concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:50-1:1) as eluent to furnish 1 g (67%) of [2-(4-methoxyphenyl)pyridin-3-yl]methanol as a colorless oil.

Step 2: Into a 50-mL round-bottom flask, was placed a solution of [2-(4-methoxyphenyl)pyridin-3-yl]methanol (1 g, 4.65 mmol, 1.00 equiv) in thionyl chloride (20 mL). The resulting solution was stirred for 2 h at reflux. The resulting mixture was concentrated under vacuum to yield 600 mg (55%) of 3-(chloromethyl)-2-(4-methoxyphenyl)pyridine as a white solid.

Step 3: Into a 50-mL round-bottom flask, was placed a solution of 3-(chloromethyl)-2-(2-methoxyphenyl)pyridine (234 mg, 1.00 mmol, 1.00 equiv), 5-hydroxy-2-methoxypyridine-4-carbaldehyde (153 mg, 1.00 mmol, 1.00 equiv), and potassium carbonate (278 mg, 2.01 mmol, 2.00 equiv) in CH₃CN (20 mL). The resulting solution was stirred for 4 h at 70° C., and then it was concentrated under vacuum. The crude product (300 mg) was purified by Prep-HPLC with the following conditions (Prep-HPLC-010): Column, SunFire Prep C18 OBD Column, 5 um, 19*150 mm; mobile phase, water with 0.1% TFA and MeCN (20.0% MeCN up to 50.0% in 10 min, up to 95.0% in 2 min, down to 20.0% in 1 min); Detector, Waters2545 UvDector 254&220 nm. This resulted in 265.1 mg (46%) of 2-methoxy-5-[[2-(4-methoxyphenyl)pyridin-3-yl]methoxy]pyridine-4-carbaldehyde; bis(trifluoroacetic acid) as a brown oil.

¹HNMR (300 MHz, DMSO-d₆) δ 10.08 (s, 1H), 8.69 (m, 1H), 8.15 (m, 2H), 7.50 (m, 1H), 7.37 (m, 1H), 7.18 (m, 2H), 7.16 (m, 1H), 6.99 (m, 1H), 5.34 (s, 2H), 3.86 (s, 3H), 3.77 (s, 3H); MS (ESI) m/z 351 [M+H]⁺.

GBT877 Preparation of 5-[[2-(2-chlorophenyl)pyridin-3-yl]methoxy]-2-methoxypyridine-4-carbaldehyde

Step 1: Into a 50-mL round-bottom flask, was placed a solution of (2-chlorophenyl)boronic acid (1.6 g, 10.23 mmol, 1.20 equiv), (2-chloropyridin-3-yl)methanol (1 g, 6.97 mmol, 1.00 equiv), Pd(dppf)Cl₂ (570 mg, 0.78 mmol, 0.10 equiv), and sodium bicarbonate (1.7 g, 20.24 mmol, 3.00 equiv) in a solvent mixture of dioxane (10 mL) and water (10 mL). The resulting solution was stirred for 3 h at 70° C., and then it was diluted with 20 mL of H₂O. The resulting solution was extracted with 2×20 mL of dichloromethane, and the combined organic layers were concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:100-1:5) as eluent to furnish 1 g (65%) of [2-(2-chlorophenyl)pyridin-3-yl]methanol as a white solid.

Step 2: Into a 25-mL round-bottom flask, was placed a solution of [2-(2-chlorophenyl)pyridin-3-yl]methanol (1 g, 4.55 mmol, 1.00 equiv) in thionyl chloride (5 mL). The resulting solution was stirred for 1 h at reflux. The resulting mixture was concentrated under vacuum to yield 1 g (92%) of 3-(chloromethyl)-2-(2-chlorophenyl)pyridine as a white solid.

Step 3: Into a 50-mL round-bottom flask, was placed a solution of 3-(chloromethyl)-2-(2-chlorophenyl)pyridine (309 mg, 1.30 mmol, 1.00 equiv), 5-hydroxy-2-methoxypyridine-4-carbaldehyde (200 mg, 1.31 mmol, 1.00 equiv), and potassium carbonate (361 mg, 2.61 mmol, 1.50 equiv) in CH₃CN (20 mL). The resulting solution was stirred for 4 h at 70° C., and then it was concentrated under vacuum. The residue was purified by prep-HPLC. This resulted in 86.2 mg (11%) of 5-[[2-(2-chlorophenyl)pyridin-3-yl]methoxy]-2-methoxypyridine-4-carbaldehyde; bis(trifluoroacetic acid) as a brown oil.

¹HNMR (300 MHz, DMSO-d₆) δ 10.06 (s, 1H), 8.69 (m, 1H), 8.19 (m, 1H), 8.05 (s, 1H), 7.56 (m, 2H), 7.41 (m, 3H), 6.92 (s, 1H), 5.14 (m, 2H), 3.81 (s, 3H); MS (ESI) m/z 355 [M+H]⁺.

GBT878 Preparation of 2-[(1-acetyl-5-phenyl-3,6-dihydro-2H-pyridin-4-yl)methoxy]-6-hydroxybenzaldehyde

Step 1: To a solution of (5-phenyl-1,2,3,6-tetrahydropyridin-4-yl)methanol hydrochloride (90 mg, 0.38 mmol) in DCM (2 mL) at 0° C. was added Et3N (0.11 mL, 0.76 mmol) and a solution of Ac2O (0.04 mL, 0.38 mmol) in DCM (0.4 mL), after stirred for 15 min, it was diluted with Sat. NH₂Cl and EtOAc, organic layer was separated and the aqueous layer was further extracted with EtOAc, organic layers were combined, washed with Sat. NaHCO₃, brine, dried over Na₂SO₄, and was concentrated to give 1-(4-(hydroxymethyl)-5-phenyl-3,6-dihydropyridin-1(2H)-yl)ethan-1-one as crude product (95 mg).

Step 2: To a solution of 1-(4-(hydroxymethyl)-3-phenyl-5,6-dihydropyridin-1(2H)-yl)ethanone (86 mg, 0.37 mmol) in DCM (2 mL) was added SOCl₂ (0.67 mL, 9.25 mmol). After stirred at RT for 15 min, the mixture was concentrated and was diluted with Sat. NaHCO₃ and EtOAc, organic layer was separated and the aqueous layer was extracted with EtOAc, organic layer ere combined, washed with brine, dried and concentrated to give crude oil, which was purified by column (Hexanes/EtOAc=100:0 to 25:75) to give 1-(4-(chloromethyl)-5-phenyl-3,6-dihydropyridin-1(2H)-yl)ethan-1-one (35 mg).

Step 3: To a suspension of K₂CO₃ (40 mg, 0.28 mmol) and 2,6-dihydroxybenzaldehyde (40 mg, 0.28 mmol) in DMF (1 mL) was added a solution of 1-(4-(chloromethyl)-5-phenyl-3,6-dihydropyridin-1(2H)-yl)ethan-1-one (35 mg, 0.14 mmol) in DMF (1 mL), the mixture was heated at 50° C. for 3 h, cooled to room temperature, and was diluted with EtOAc, organic layer was separated and aqueous layer was extracted with EtOAc. EtOAc layers were combined, washed with Sat. NaHCO₃, brine, dried over Na₂SO₄, and was concentrated to give crude oil, which was purified by column (DCM/MeOH=90:10) to give 2-((1-acetyl-5-phenyl-1,2,3,6-tetrahydropyridin-4-yl)methoxy)-6-hydroxybenzaldehyde (17 mg). 1H NMR (400 MHz, CDCl₃, NMR shows rotamer exist, only one set of signal was reported) □ (ppm) 11.93 (s, 1H), 10.36 (s, 1H), 7.34 (m, 5H), 7.22 (m, 1H), 6.49 (d, J=8.8 Hz, 1H), 6.10 (d, J=8.8 Hz, 1H), 4.47 (s, 2H), 4.32 (s, 2H), 3.68 (t, J=6.0 Hz, 2H), 2.47 (m, 2H), 2.18 (s, 3H); MS (ESI) m/z 352.5 [M+H]⁺.

GBT881 Preparation of 2-[(1-acetyl-4-phenyl-3,6-dihydro-2H-pyridin-5-yl)methoxy]-6-hydroxybenzaldehyde

Step 1: To a solution of 1-tert-butyl 3-methyl 4-oxopiperidine-1,3-dicarboxylate (2.50 g, 9.72 mmol) in DCM (50 mL) was added DIPEA (2.03 mL, 11.66 mmol) and Tf₂O (1.80 mL, 10.69 mmol) at −78° C., and then it was warmed up to room temperature and stirred further for 2 h, the solution was diluted with DCM and the organic layer was washed with Sat. NaHCO₃, dried and concentrated to give 1-tert-butyl 3-methyl 4-(((trifluoromethyl)sulfonyl)oxy)-5,6-dihydropyridine-1,3(2H)-dicarboxylate as crude product (4.4 g).

Step 2: To a solution of 1-tert-butyl 3-methyl 4-(((trifluoromethyl)sulfonyl)oxy)-5,6-dihydropyridine-1,3(2H)-dicarboxylate (1.95 g, 5 mmol) and phenylboronic acid (1.22 g, 10 mmol) in Dioxane (20 ml) was added Pd(dppf)Cl₂ and a solution of Na₂CO₃ (3.18 g, 30 mmol) in water (6 mL), after degassed with N₂ for 5 min, the reaction was heated at 100° C. for 15 h, the mixture was cooled to room temperature, diluted with EtOAc, organic layer was washed with water, brine, dried and concentrated to give crude product, which was purified by column (Hexanes/EtOAc=3:1) to give 1-tert-butyl 3-methyl 4-phenyl-5,6-dihydropyridine-1,3(2H)-dicarboxylate (740 mg).

Step 3: To a solution of 1-tert-butyl 3-methyl 4-phenyl-5,6-dihydropyridine-1,3(2H)-dicarboxylate (740 mg, 2.33 mmol) in THF (7.2 mL) was added 1M LiAlH₄ in THF (2.80 mL, 2.80 mmol) at −20° C. dropwise, after stirring at −20° C. for 30 min, it was quenched with Sat. NH₄Cl, the mixture was extracted with EtOAc. Organic layers were combined, washed with brine, dried and concentrated to give crude product, which was purified by column (Hexanes/EtOAc=60:40) to give tert-butyl 5-(hydroxymethyl)-4-phenyl-3,6-dihydropyridine-1(2H)-carboxylate (312 mg).

Step 4: To tert-butyl 3-(hydroxymethyl)-4-phenyl-5,6-dihydropyridine-1(2H)-carboxylate (310 mg, 1.76 mmol) was added 4N HCl in Dioxane (3 ml), after stirring at room temperature for 1 h, it was concentrated to give (4-phenyl-1,2,3,6-tetrahydropyridin-3-yl)methanol as HCl salt.

Step 5: To a solution of (4-phenyl-1,2,3,6-tetrahydropyridin-3-yl)methanol hydrochloride (110 mg, 0.49 mmol) in DCM (2 mL) was added DIPEA (0.17 mL, 0.98 mmol) and Ac₂O (0.03 g, 0.49 mmol), 13 min later, it was diluted with water and extracted with DCM. Organic layers were combined, dried and concentrated, the resulting crude oil was purified by column (EtOAc followed by DCM/MeOH=9:1) to give 1-(5-(hydroxymethyl)-4-phenyl-3,6-dihydropyridin-1(2H)-yl)ethan-1-one (88 mg).

Step 6: To a solution of 1-(3-(hydroxymethyl)-4-phenyl-5,6-dihydropyridin-1(2H)-yl)ethanone (88 mg, 0.38 mmol) in DCM (2 mL) was added SOCl₂ (0.67 mL, 9.50 mmol) at 0° C. After stirring at 0° C. for 15 min, the solution was concentrated to remove SOCl₂, dried under high vacuum to give 1-(5-(chloromethyl)-4-phenyl-3,6-dihydropyridin-1(2H)-yl)ethan-1-one as crude product.

Step 7: To a solution of 1-(3-(chloromethyl)-4-phenyl-5,6-dihydropyridin-1(2H)-yl)ethanone (100 mg, 0.40 mmol) and 2,6-dihydroxybenzaldehyde (110 mg, 0.80 mmol) in DMF (2.5 mL) was added K₂CO₃ (170 mg, 1.20 mmol), after heated at 50 degree for 2 h, the reaction was diluted with EtOAc, organic layer was separated and aqueous layer was extracted with EtOAc. EtOAc layers were combined, washed with Sat. NaHCO₃, brine, dried over Na₂SO₄, and was concentrated to give crude oil, which was purified by preparative HPLC (eluted with ACN/H₂O) to give 2-((1-acetyl-4-phenyl-1,2,5,6-tetrahydropyridin-3-yl)methoxy)-6-hydroxybenzaldehyde (26 mg). 1H NMR (400 MHz, CDCl₃, NMR shows rotamers exist, only one set of signal was reported) δ (ppm) 11.97 (s, 1H), 10.34 (s, 1H), 7.34 (m, 4H), 7.17 (m, 2H), 6.49 (d, J=8.0 Hz, 1H), 6.11 (d, J=8.8 Hz, 1H), 4.48 (s, 2H), 4.33 (s, 2H), 3.69 (t, J=6.0 Hz, 2H), 2.55 (m, 2H), 2.18 (s, 3H); MS (ESI) m/z 352.3 [M+H]⁺.

GBT887 Preparation of 2-((2-(1-cyclopentyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-6-hydroxybenzaldehyde

To a mixture of 3-(chloromethyl)-2-(1-cyclopentyl-1H-pyrazol-5-yl)pyridine hydrochloride (44.7 mg, 0.15 mmol) and 2,6-dihydroxybenzaldehyde (83 mg, 0.6 mmol, 4 eq) and potassium carbonate (41.5 mg, 0.3 mmol, 2 eq) were added 1 mL anhydrous DMF. The mixture was heated to 80° C. for 40 mins. The reaction was almost done by LCMS. Solvent was removed at 50° C. on a rotavap. Water 3 mL and 0.3 mL of formic acid were added to the resulting brown residue, the mixture was sonicated to make sure all carbonate was neutralized. Solvents were then removed at 45° C. on a rotavap. DCM (4×1 ml) was added to the yellow residue, the mixture was sonicated and filtered. The filtrate was concentrated to give the crude product as a yellow-light brown film. It contains the product, 2,6-dihydroxybenzaldehyde, and some starting chloride, no bis-alkylation product was observed. The residue was taken up in 2 ml DCM, filtered and loaded on a 4 g ZAP SiO₂ column. It was purified on Biotage Isolera One system eluted with 5%-100% EtOAc (the product came out around 25% EtOAc, 2nd peak; the 1st peak is dihydroxybenzaldehyde). The product as a yellow film was obtained after removing solvents, the residue was re-dissolved in 0.3 mL CH₃CN and to this was added 0.5 mL of water. This suspension was free zed and put on a lyophilizer over the weekend. The product was obtained as a light brown film (18.6 mg, 34% yield). ¹H NMR (400 MHz, CDCl₃-d) δ 11.94 (s, 1H), 10.37 (s, 1H), 8.75 (dd, J=4.8, 1.7 Hz, 1H), 7.97 (dd, J=8.0, 1.4 Hz, 1H), 7.59 (d, J=2.0 Hz, 1H), 7.42 (dd, J=7.7, 4.8 Hz, 1H), 7.37 (t, J=8.3 Hz, 1H), 6.56 (d, J=8.6 Hz, 1H), 6.35 (d, J=1.9 Hz, 1H), 6.25 (d, J=8.3 Hz, 1H), 5.07 (s, 2H), 4.79-4.67 (m, 1H), 2.18-1.95 (m, 4H), 1.95-1.84 (m, 2H), 1.66-1.50 (m, 2H); MS (ESI) m/z 364.3 [M+H]⁺.

GBT888 Preparation of 2-hydroxy-6-[[(2S)-1-phenylpyrrolidin-2-yl]methoxy]benzaldehyde

Step 1: To a solution of (S)-pyrrolidin-2-ylmethanol (1.52 g, 15 mmol) and CuI (190 mg, 1 mmol) in iPrOH (10 mL) was added (CH₂OH)₂ (1.11 mL, 20 mmol), iodobenzene (2.04 g, 20 mmol) and K₃PO₄ (4.25 g, 20 mmol), after degassed with N2, the mixture was heated at 88° C. for 15 h. Water and ether was added, organic layer was separated and aqueous layer was further extracted with ether. Organic layers were combined, concentrated and the resulting crude oil was purified by column (hexanes/EtOAc=2:1) to give (S)-(1-phenylpyrrolidin-2-yl)methanol (1.6 g).

Step 2: To a solution of (S)-(1-phenylpyrrolidin-2-yl)methanol (45 mg, 0.23 mmol) and 2,6-dihydroxybenzaldehyde (60 mg, 0.46 mmol) in THF (1 ml) was added PPh₃ (0.12 g, 0.46 mmol), followed by DIAD (90 mg, 0.46 mmol) at room temperature. After stirrer for 10 min, the mixture was concentrated and the residue was purified by column (Hexanes/EtOAc=9:1) to give (S)-2-hydroxy-6-((1-phenylpyrrolidine-2-yl)methoxy)benzaldehyde (14 mg). 1H NMR (400 MHz, CDCl₃ (ppm) 11.96 (s, 1H), 10.37 (s, 1H), 7.35 (t, J=8.0 Hz, 1H), 7.25 (m, 2H), 6.73 (m, 3H), 6.53 (d, J=8.4 Hz, 1H), 6.33 (d, J=9.2 Hz, 1H), 4.21 (m, 1H), 4.15 (d, J=3.6 Hz, 1H), 3.83 (t, J=8.0 Hz, 1H), 3.53 (m, 1H), 3.22 (m, 1H), 2.11 (m, 4H); MS (ESI) m/z 298.4

GBT892 Preparation of 5-[[2-(3-chlorophenyl)pyridin-3-yl]methoxy]-2-methoxypyridine-4-carbaldehyde

Step 1: Into a 50-mL round-bottom flask, was placed a solution of (3-chlorophenyl)boronic acid (1.6 g, 10.23 mmol, 1.20 equiv), (2-chloropyridin-3-yl)methanol (1 g, 6.97 mmol, 1.00 equiv), Pd(dppf)Cl₂ (370 mg, 0.78 mmol, 0.10 equiv), and sodium bicarbonate (1.7 g, 20.24 mmol, 3.00 equiv) in a solvent mixture of dioxane (10 mL) and water (10 mL). The resulting solution was stirred for 3 h at 70° C., and then it was diluted with 20 mL of H₂O. The resulting solution was extracted with 2×20 mL of dichloromethane, and the combined organic layers were concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:100-1:5) as eluent to yield 1.2 g (78%) of [2-(3-chlorophenyl)pyridin-3-yl]methanol as a white solid.

Step 2: Into a 50-mL round-bottom flask, was placed a solution of [2-(3-chlorophenyl)pyridin-3-yl]methanol (600 mg, 2.73 mmol, 1.00 equiv) in thionyl chloride (10 mL). The resulting solution was stirred for 1 h at reflux. The resulting mixture was concentrated under vacuum. This resulted in 500 mg (77%) of 3-(chloromethyl)-2-(3-chlorophenyl)pyridine as a white solid.

Step 3: Into a 50-mL round-bottom flask, was placed a solution of 3-(chloromethyl)-2-(3-chlorophenyl)pyridine (309 mg, 1.30 mmol, 1.00 equiv), 5-hydroxy-2-methoxypyridine-4-carbaldehyde (200 mg, 1.31 mmol, 1.00 equiv), and potassium carbonate (361 mg, 2.61 mmol, 2.00 equiv) in CH₃CN (20 mL). The resulting solution was stirred for 4 h at 70° C., and then it was concentrated under vacuum. The crude product (300 mg) was purified by Prep-HPLC with the following conditions (Prep-HPLC-010): Column, SunFire Prep C18 OBD Column, 5 um, 19*150 mm; mobile phase, water with 0.05% TFA and MeCN (20.0% MeCN up to 60.0% in 10 min, up to 95.0% in 2 min, down to 20.0% in 1 min); Detector, Waters2545 UvDector 254&220 nm. This resulted in 71 mg (9%) of 5-[[2-(3-chlorophenyl)pyridin-3-yl]methoxy]-2-methoxypyridine-4-carbaldehyde; bis(trifluoroacetic acid) as a yellow solid.

¹HNMR (400 MHz, DMSO-d6) δ 10.07 (s, 1H), 8.72 (m, 1H), 8.20 (m, 2H), 7.79 (s, 1H), 7.60 (m, 4H), 6.95 (m, 1H), 5.21 (m, 2H), 3.85 (s, 3H); MS (ESI) m/z 355 [M+H]⁺.

GBT893 Preparation of 5-[[2-(4-chlorophenyl)pyridin-3-yl]methoxy]-2-methoxypyridine-4-carbaldehyde

Step 1: Into a 100-mL round-bottom flask, was placed a solution of (4-chlorophenyl)boronic acid (1.6 g, 10.23 mmol, 1.20 equiv), (2-chloropyridin-3-yl)methanol (1 g, 6.97 mmol, 1.00 equiv), Pd(dppf)Cl₂ (370 mg, 0.78 mmol, 0.10 equiv), and sodium bicarbonate (1.7 g, 20.24 mmol, 3.00 equiv) in a solvent mixture of dioxane (10 mL) and water (10 mL). The resulting solution was stirred for 4 h at 70° C., and then it was diluted with 100 mL of H₂O. The resulting solution was extracted with 2×200 mL of dichloromethane, and the combined organic layers were concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:100-1:3) as eluent to yield 1 g (63%) of [2-(4-chlorophenyl)pyridin-3-yl]methanol as a light yellow oil.

Step 2: Into a 23-mL round-bottom flask, was placed a solution of [2-(4-chlorophenyl)pyridin-3-yl]methanol (1 g, 4.33 mmol, 1.00 equiv) in thionyl chloride (3 mL). The resulting solution was stirred for 1 h at reflux. The resulting mixture was concentrated under vacuum. This resulted in 1 g (92%) of 3-(chloromethyl)-2-(4-chlorophenyl)pyridine as a white solid.

Step 3: Into a 30-mL round-bottom flask, was placed a solution of 3-(chloromethyl)-2-(4-chlorophenyl)pyridine (309 mg, 1.30 mmol, 1.00 equiv), 5-hydroxy-2-methoxypyridine-4-carbaldehyde (200 mg, 1.31 mmol, 1.00 equiv), and potassium carbonate (361 mg, 2.61 mmol, 2.00 equiv) in CH₃CN (20 mL). The resulting solution was stirred for 4 h at 70° C., and then it was concentrated under vacuum. The crude product (300 mg) was purified by Prep-HPLC with the following conditions (Prep-HPLC-010): Column, SunFire Prep C18 OBD Column, 5 um, 19*150 mm; mobile phase, water with 0.05% TFA and MeCN (20.0% MeCN up to 60.0% in 10 min, up to 95.0% in 2 min, down to 20.0% in 1 min); Detector, Waters2545 UvDector 254&220 nm. This resulted in 148.2 mg (20%) of 5-[[2-(4-chlorophenyl)pyridin-3-yl]methoxy]-2-methoxypyridine-4-carbaldehyde; bis(trifluoroacetic acid) as a yellow solid.

¹HNMR (300 MHz, DMSO-d₆) δ 10.05 (s, 1H), 8.69 (m, 1H), 8.16 (m, 2H), 7.64 (m, 2H), 7.50 (m, 3H), 5.32 (s, 2H), 3.81 (s, 3H); MS (ESI) m/z 355 [M+H]⁺.

(R)-2-hydroxy-6-((1-phenylpyrrolidin-2-yl)methoxy)benzaldehyde

GBT903—Preparation of (R)-2-hydroxy-6-((1-phenylpyrrolidin-2-yl)methoxy)benzaldehyde. The compound was prepared from (R)-pyrrolidin-2-ylmethanol and iodobenzene according to scheme 8, reaction steps 3 and 4. ¹H NMR (400 MHz, Chloroform-d) δ 11.96 (d, J=0.4 Hz, 1H), 10.37 (s, 1H), 7.37 (td, J=8.4, 0.4 Hz, 1H), 7.31-7.18 (m, 2H), 6.77-6.64 (m, 3H), 6.53 (dt, J=8.5, 0.7 Hz, 1H), 6.33 (dd, J=8.3, 0.8 Hz, 1H), 4.25-4.12 (m, 2H), 3.88-3.78 (m, 1H), 3.53 (dt, J=8.8, 4.4 Hz, 1H), 3.27-3.16 (m, 1H), 2.11 (dqt, J=13.0, 6.4, 2.8 Hz, 4H). MS (M+H)+ found for C₁₈H₁₉NO₃: 298.2.

2-hydroxy-6-((2-(1-methyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde

GBT904—Preparation of 2-hydroxy-6-((2-(1-methyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde. The compound was prepared from (2-chloropyridin-3-yl)methanol and 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole according to scheme 9, reaction steps 1, 2 and 4. In step 4, 2-hydroxy-6-(methoxymethoxy)benzaldehyde was used; the MOM ether protecting group fell off after the reaction to give the final product. ¹H NMR (400 MHz, Chloroform-d) δ 11.94 (s, 1H), 10.36 (s, 1H), 8.75 (dd, J=4.8, 1.7 Hz, 1H), 7.98 (d, J=8.0 Hz, 1H), 7.54 (d, J=1.9 Hz, 1H), 7.41 (dd, J=8.0, 4.0 Hz, 1H), 7.38 (t, J=8.0 Hz, 1H), 6.58 (dt, J=8.5, 0.7 Hz, 1H), 6.39 (d, J=1.9 Hz, 1H), 6.28 (dd, J=8.3, 0.8 Hz, 1H), 5.12 (s, 2H), 3.95 (s, 3H). MS (M+H) found for C₁₇H₁₅N₃O₃: 310.3.

GBT907 and GBT908—Preparation of (S)-2-hydroxy-6-((1-(2-methoxyphenyl)pyrrolidin-2-yl)methoxy)benzaldehyde (GBT907) and 2-hydroxy-6-((1-(2-methoxyphenyl)piperidin-3-yl)oxy)benzaldehyde (GBT908). The reaction of (S)-pyrrolidin-2-ylmethanol with 2-iodoanisole, and subsequent Mitsunobu reaction, according to scheme 8, gave a mixture of GBT907 and GBT908 in 3:2 ratio, which were separated by reverse-phase prep HPLC.

GBT907—(S)-2-hydroxy-6-((1-(2-methoxyphenyl)pyrrolidin-2-yl)methoxy)benzaldehyde ¹H NMR (400 MHz, Chloroform-d) δ 11.96 (d, J=0.4 Hz, 1H), 10.37 (d, J=0.6 Hz, 1H), 7.39 (td, J=8.4, 0.4 Hz, 1H), 7.04-6.87 (m, 3H), 6.84 (dd, J=8.0, 1.4 Hz, 1H), 6.52 (ddt, J=13.7, 8.4, 0.7 Hz, 2H), 4.66 (tt, J=8.2, 3.9 Hz, 1H), 3.80 (s, 3H), 3.67-3.58 (m, 1H), 3.29 (dt, J=9.9, 4.3 Hz, 1H), 2.85 (dd, J=11.3, 8.3 Hz, 1H), 2.82-2.74 (m, 1H), 2.20 (dd, J=12.4, 4.9 Hz, 1H), 2.00 (dp, J=13.0, 4.6 Hz, 1H), 1.94-1.79 (m, 1H), 1.72 (dddd, J=13.0, 10.7, 9.0, 4.3 Hz, 1H). MS (M+H)+ found for C₁₉H₂₁NO₄: 328.3).

GBT908—2-hydroxy-6-((1-(2-methoxyphenyl)piperidin-3-yl)oxy)benzaldehyde (40 mg, ¹H NMR (400 MHz, Chloroform-d) δ 11.91 (s, 1H), 10.09 (d, J=0.6 Hz, 1H), 7.32 (d, J=8.4 Hz, 1H), 6.93-6.80 (m, 4H), 6.46 (dt, J=8.5, 0.7 Hz, 1H), 6.23 (dd, J=8.4, 0.8 Hz, 1H), 4.49 (tt, J=7.2, 4.7 Hz, 1H), 4.06 (dd, J=9.3, 4.4 Hz, 1H), 3.88-3.78 (m, 1H), 3.80 (s, 3H), 3.63 (ddd, J=9.1, 7.3, 6.3 Hz, 1H), 3.21-3.11 (m, 1H), 2.35-2.22 (m, 1H), 2.09-1.86 (m, 3H), MS (M+H)+ found for C₁₉H₂₁NO₄: 328.3).

2-(((3S,4R)-1-acetyl-4-(2,5-difluorophenyl)pyrrolidin-3-yl)methoxy)-6-hydroxybenzaldehyde

GBT912—2-(((3S,4R)-1-acetyl-4-(2,5-difluorophenyl)pyrrolidin-3-yl)methoxy)-6-hydroxybenzaldehyde. The compound was prepared from -(2,5-difluorophenyl)-4-(hydroxymethyl)pyrrolidin-1-yl)ethan-1-one and 2,6-dihydroxybenzaldehyde (INT-7) using general method A (Mitsunobu conditions). ¹H NMR (400 MHz, Chloroform-d) δ 11.90 (s, 1H), 9.88 (s, 1H), 7.37 (dd, J=8.4, 6.4 Hz, 1H), 7.01 (m, 3H), 6.53 (t, J=8.6 Hz, 1H), 6.27 (dd, J=8.3, 0.8 Hz, 1H), 4.02 (m, 4H), 3.55 (m, 3H), 2.96 (m, 1H), 2.11 (s, 3H). MS (M+H)+ found for C₂₀H₁₉F₂NO₄: 376.3.

Preparation of -(2,5-difluorophenyl)-4-(hydroxymethyl)pyrolidin-1-yl)ethan-1-one

To a solution of ((3S,4R)-4-(2,5-difluorophenyl)pyrrolidin-3-yl)methanol hydrochloride (200 mg, 0.8 mmol) in DCM (2 mL) at 0° C. was added DIPEA (0.3 mL, 1.68 mmol) and Ac₂O (90 mg, 0.84 mmol), after stirred for 30 min, the solution was diluted with DCM, organic layer was washed with Sat. NaHCO₃, brine, dried over MgSO₄ and was concentrated to give 1-((3R,4S)-3-(2,5-difluorophenyl)-4-(hydroxymethyl)pyrrolidin-1-yl)ethan-1-one as crude product (175 mg).

GBT913 and GBT914

GBT913 and GBT914—Preparation of (S)-2-hydroxy-6-((1-(3-methoxyphenyl)pyrrolidin-2-yl)methoxyl)benzaldehyde (GBT913) and 2-hydroxy-6-((1-(3-methoxyphenyl)piperidin-3-yl)oxy)benzaldehyde (GBT914). The reaction of (S)-pyrrolidin-2-ylmethanol with 3-iodoanisole, and subsequent Mitsunobu reaction, according to scheme 8, gave a mixture of GBT913 and GBT914 in 3:4 ratio, which were separated by reverse-phase prep HPLC.

GBT913—(S)-2-hydroxy-6-((1-(3-methoxyphenyl)pyrrolidin-2-yl)methoxy)benzaldehyde ¹H NMR (400 MHz, Chloroform-d) δ 11.95 (s, 1H), 10.37 (t, J=0.5 Hz, 1H), 7.42-7.31 (m, 1H), 7.16 (t, J=8.2 Hz, 1H), 6.53 (dq, J=8.4, 0.6 Hz, 1H), 6.36-6.24 (m, 3H), 6.23 (t, J=2.4 Hz, 1H), 4.23-4.12 (m, 2H), 3.79 (s, 4H), 3.50 (ddd, J=9.0, 5.6, 3.5 Hz, 1H), 3.27-3.16 (m, 1H), 2.17-1.98 (m, 4H). MS (M+H)+ found for C₁₉H₂₁NO₄: 328.3

GBT914—2-hydroxy-6-((1-(3-methoxyphenyl)piperidin-3-yl)oxy)benzaldehyde ¹H NMR (400 MHz, Chloroform-d) δ 11.94 (d, J=0.4 Hz, 1H), 10.25 (d, J=0.6 Hz, 1H), 7.39 (td, J=8.4, 0.4 Hz, 1H), 7.19-7.08 (m, 1H), 6.51 (dt, J=8.5, 0.7 Hz, 2H), 6.48-6.37 (m, 3H), 4.58 (m, 1H), 3.78 (m, 1H), 3.77 (s, 3H), 3.74-3.64 (m, 1H), 3.39 (d, J=5.6 Hz, 1H), 3.17 (dd, J=12.4, 7.6 Hz, 1H), 3.11-3.01 (m, 1H), 2.14 (s, 1H), 2.02-1.92 (m, 1H), 1.86-1.74 (m, 1H). MS (M+H)+ found for C₁₉H₂₁NO₄: 328.4).

GBT916—2-hydroxy-6-((2-(2-methoxyphenyl)pyridin-3-yl)methoxy)benzaldehyde. The compound was prepared from (2-chloropyridin-3-yl)methanol and (2-methoxyphenyl)boronic acid according to scheme 9, reaction steps 1, 2 and 4. In step 4, alkylation with 2,6-dihydroxybenzaldehyde, the product of TFA salt was obtained after HPLC purification. ¹HNMR (300 MHz, DMSO, ppm): 11.71 (s, 1H), 9.99 (s, 1H), 8.65 (m, 1H), 8.13 (d, J=7.5 Hz, 1H), 7.50 (m, 3H), 7.31 (m, 1H), 7.04 (m, 2H), 6.47 (m, 1H) 6.38 (m, d, J=8.4 Hz, 1H), 5.00 (s, 2H), 3.73 (s, 3H); MS (ES, m/z): 336 [M+H]⁺.

GBT917—2-hydroxy-6-((2′-methoxy-[2,3′-bipyridin]-3-yl)methoxy)benzaldehyde. The compound was prepared from (2-chloropyridin-3-yl)methanol and (2-methoxypyridin-3-yl)boronic acid according to scheme 9, reaction steps 1, 2 and 4. In step 4, alkylation with 2,6-dihydroxybenzaldehyde, the product TFA salt was obtained after HPLC purification.

¹HNMR (300 MHz, CDCl3, ppm): 11.91 (s, 1H), 10.24 (s, 1H), 8.71 (t, 1H), 8.69 (m, 1H), 7.93 (d, 1H), 7.75 (d, 1H), 7.40 (m, 1H), 7.39 (m, 1H), 7.08 (m, 1H), 6.53 (d, 1H), 6.50 (d, 1H), 5.07 (s, 2H), 3.94 (s, 3H); MS (ES, m/z): 337 [M+H]⁺

GBT930—2-((2-(1-cyclobutyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-6-hydroxybenzaldehyde. The compound was prepared by Mitsunobu reaction (scheme 9, step 3) of (2-(1-cyclobutyl-1H-pyrazol-5-yl)pyridin-3-yl)methanol (A) with 2,6-dihydroxybenzaldehyde (INT3). The product was obtained as pale yellow solid. ¹HNMR (300 MHz, CDCl3, ppm): 11.95 (s, 1H), 10.35 (s, 1H), 8.75 (m, 1H), 7.97 (d, J=7.2 Hz, 1H), 7.62 (m, 1H), 7.45 (m, 1H), 7.36 (m, 1H), 6.56 (d, J=8.4 Hz, 1H), 6.38 (m, 1H), 6.23 (d, J=8.4 Hz, 1H), 5.07 (s, 2H), 4.85 (m, 1H), 2.75 (m, 2H), 2.27 (m, 2H), 1.25 (m, 2H); (ES, m/z): 350 [M+H]⁺

Preparation of intermediate A. Intermediate A was prepared from pyrazole in three steps according scheme below.

Step 1: Into a 500-mL round-bottom flask, was placed a solution of 1H-pyrazole (10 g, 146.89 mmol, 1.00 equiv), Cs₂CO₃ (95.9 g, 294.33 mmol, 2.00 equiv), and bromocyclobutane (29.7 g, 220.00 mmol, 1.50 equiv) in CH₃CN (150 mL). The resulting solution was stirred overnight at 80° C., and then it was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:400-1:200) as eluent to yield 8 g (45%) of 1-cyclobutyl-1H-pyrazole as a colorless liquid.

Step 2: Into a 250-mL round-bottom flask, was placed a solution of 1-cyclobutyl-1H-pyrazole (6.5 g, 53.21 mmol, 1.00 equiv) in tetrahydrofuran (100 ml). This was followed by the addition of BuLi (2.5 M, 22.7 mL, 1.10 equiv) dropwise with stirring at −30° C. The mixture was stirred for 30 min at the same temperature. To this was added 4,4,5,5-tetramethyl-2-(propan-2-yloxy)-1,3,2-dioxaborolane (14.9 g, 80.08 mmol, 1.50 equiv) dropwise with stirring at −78° C. The resulting solution was stirred for 3 h at −78° C., and then it was quenched by the addition of 30 mL of water. The resulting solution was extracted with 2×200 mL of dichloromethane. The combined organic layers were concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:200-1:30) as eluent to furnish 6.2 g (47%) of 1-cyclobutyl-5-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole as a colorless oil.

Step 3: Into a 100-mL round-bottom flask, was placed a solution of 1-cyclobutyl-5-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (791 mg, 3.19 mmol, 2.00 equiv), (2-bromopyridin-3-yl)methanol (500 mg, 2.66 mmol, 1.00 equiv), Pd(dppf)Cl₂ (217 mg, 0.30 mmol, 0.10 equiv), and sodium carbonate (670 mg, 6.32 mmol, 3.00 equiv) in a solvent mixture of dioxane (10 mL) and water (10 mL). The resulting solution was stirred for 2 h at 80° C. The resulting solution was extracted with 3×20 mL of dichloromethane. The combined organic layers were concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:3-1:1) as eluent to provide 200 mg (33%) of [2-(1-cyclobutyl-1H-pyrazol-5-yl)pyridin-3-yl]methanol as a yellow oil.

GBT934—2-((2′-ethoxy-[2,3′-bipyridine]-3-yl)methoxy)-6-hydroxybenzaldehyde The compound was prepared from (2-chloropyridin-3-yl)methanol and ((2-ethoxypyridin-3-yl)boronic acid according to scheme 9, reaction steps 1, 2 and 4. In step 4, alkylation with 2,6-dihydroxybenzaldehyde (INT3), the product TFA salt as white solid was obtained after HPLC purification. ¹HNMR (400 MHz, CDCl₃, ppm): 11.91 (br s, 1H), 10.29 (s, 1H), 8.97 (s, 2H), 8.97 (br s, 1H), 8.46 (d, J=8.0 Hz, 1H), 8.40 (d, J=4.8 Hz, 1H), 7.87 (s, 1H), 7.81 (d, J=6.8 Hz, 1H), 7.53 (t, J=4.4 Hz, 1H), 7.12 (t, J=6.0 Hz, 1H), 6.59 (d, J=8.4 Hz, 1H), 6.14 (d, J=8.4 Hz, 1H), 5.17 (s, 2H), 4.46 (q, J=6.8 Hz, 2H), 1.32 (t, J=6.8 Hz, 3H); MS (ES, m/z:) 351.1 [M+H]⁺

GBT948—3-chloro-2-hydroxy-6-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde. The compound was prepared using general reaction step 4 of scheme 9, by O-alkylation of 3-chloro-6-hydroxy-2-(methoxymethoxy)benzaldehyde (B) with 3-(chloromethyl)-2-(1-isopropyl-1H-pyrazol-5-yl)pyridine (A) and subsequent deprotection of the MOM ether by treating with aqueous 6N HCl in THF. ¹HNMR (400 MHz, CDCl₃, ppm): 12.49 (s, 1H), 10.34 (s, 1H), 8.80 (dd, J=3.6 Hz, 1H), 8.00 (dd, J=5.7 Hz, 1H), 7.63 (d, J=1.2 Hz, 1H), 7.47 (m, 2H), 6.36 (m, 2H), 5.11 (d, J=10.8 Hz, 2H), 4.70 (in, 1H), 4.61 (m, 1H), 1.53 (d, J=4.5 Hz, 6H); MS (ES, m/f): 372[M+1]⁺

The MOM-protected phenol aldehyde intermediate B was prepared according to the following synthetic scheme:

Step 1: Into a 2000-mL round-bottom flask, was placed a solution of 4-chlorobenzene-1,3-diol (50.0 g, 345.89 mmol, 1.00 equiv) and potassium carbonate (95 g, 687.36 mmol, 2.00 equiv) in acetone (1000 mL). This was followed by the addition of MOMBr (40 g, 320.10 mmol, 0.90 equiv) dropwise with stirring. The resulting solution was stirred for 60 h at room temperature. The solids were filtered out. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:10-1:2) as eluent to furnish 49 g (75%) of 4-chloro-3-(methoxymethoxy)phenol as a colorless oil.

Step 2: Into a 1000-mL round-bottom flask, was placed a solution of 4-chloro-3-(methoxymethoxy)phenol (49.0 g, 259.80 mmol, 1.00 equiv) and potassium carbonate (57.4 g, 415.31 mmol, 1.60 equiv) in acetone (500 mL). This was followed by the addition of BnBr (55 g, 321.58 mmol, 1.20 equiv) dropwise with stirring in 40 min. The resulting solution was stirred overnight at room temperature. The solids were filtered out. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:99-1:10-1:2) as eluent to furnish 40.0 g (55%) of 4-(benzyloxy)-1-chloro-2-(methoxymethoxy)benzene as a colorless oil.

Step 3: Into a 500-mL three neck round-bottom flask, was placed a solution of bis(propan-2-yl)amine (29.7 g, 293.31 mmol, 3.00 equiv) in tetrahydrofuran (70 mL). This was followed by the addition of BuLi (100 mL, 3.00 equiv) dropwise with stirring at −78° C. The mixture was stirred for 10 min at −78° C., then stirred for 10 min at 0° C. To this was added a solution of 4-(benzyloxy)-1-chloro-2-(methoxymethoxy)benzene (23.3 g, 83.39 mmol, 1.00 equiv) in tetrahydrofuran (70 mL) dropwise with stirring at −78° C. The mixture was stirred for 1 h at −40° C. To the mixture was added N,N-dimethylformamide (18.3 g, 230.38 mmol, 3.00 equiv) dropwise with stirring at −78° C. The resulting solution was stirred for 30 min at −78° C. The reaction was then quenched by the addition of 30 mL of NH₄Cl (aq). The resulting solution was diluted with 30 mL of water. The resulting solution was extracted with 3×100 mL of ethyl acetate and the organic layers combined and dried over sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:3) as eluent. This resulted in 8.8 g (34%) of 6-(benzyloxy)-3-chloro-2-(methoxymethoxy)benzaldehyde as a yellow solid.

Step 4: Into a 500-mL round-bottom flask, was placed a solution of 6-(benzyloxy)-3-chloro-2-(methoxymethoxy)benzaldehyde (8.8 g, 28.69 mmol, 1.00 equiv) in ethyl acetate (100 mL). Rh/C (1.0 g) was added to the reaction. The resulting solution was stirred for 20 h at room temperature under 1 atm of hydrogen gas. The solids were filtered out. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:2) as eluent. This resulted in 5.2 g (84%) of 3-chloro-6-hydroxy-2-(methoxymethoxy)benzaldehyde as a light yellow solid.

GBT954—4-hydroxy-2-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde. The compound was prepared by Mitsunobu reaction (scheme 9, step 3) of 2-hydroxy-4-(methoxymethoxy)benzaldehyde (A) with (2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methanol (B) and subsequent deprotection of the MOM ether by treating with aqueous 6N HCl in THF according the scheme below. ¹HNMR (400 MHz, DMSO, ppm): 10.70 (s, 1H), 10.09 (s, 1H), 8.75 (m, 1H), 8.22 (d, J=8 Hz, 1H), 7.59 (m, 3H), 6.52 (m, 3H), 5.16 (s, 2H), 4.65 (m, 1H), 1.37 (m, 6H); (ES, m/z): 338 [M+H]⁺

Preparation of intermediate 2-hydroxy-4-(methoxymethoxy)benzaldehyde

Into a 100-mL round-bottom flask, was placed a solution of 2,4-dihydroxybenzaldehyde (3 g, 21.72 mmol, 1.00 equiv), MOMBr (3.2 g, 25.60 mmol, 1.20 equiv), and potassium carbonate (3.9 g, 28.22 mmol, 1.30 equiv) in acetone (20 mL). The resulting solution was stirred overnight at room temperature. The resulting solution was diluted with 30 mL of H₂O. The resulting solution was extracted with 3×20 mL of dichloromethane and the organic layers combined and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:50-1:30) as eluent to furnish 2.6 g (66%) of 2-hydroxy-4-(methoxymethoxy)benzaldehyde as a white solid.

GBT967—2-((2′,6′-dimethoxy-[23′-bipyridin]-3-yl)methoxy)-6-hydroxybenzaldehyde. The compound was prepared from (2-chloropyridin-3-yl)methanol and 2,6-dimethoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine according to scheme 9, reaction steps 1, 2 and 4. In step 4, alkylation with 2,6-dihydroxybenzaldehyde, the product of TFA salt as white solid was obtained after HPLC purification. ¹HNMR (400 MHz, DMSO, ppm): 10.04 (s, 1H), 8.65 (m, 1H), 8.14 (d, J=7.6 Hz, 1H), 7.73 (d, J=8 Hz, 1H), 7.51 (m, 2H), 6.50 (m, 3H), 5.16 (m, 2H), 3.91 (s, 1H), 3.86 (s, 1H); (ES, m/z): 367 [M+H]⁺

GBT985—3-(difluoromethyl)-1-methyl-5-((2-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-1H-pyrazole-4-carbaldehyde

3-(Difluoromethyl)-5-hydroxy-1-methyl-1H-pyrazole-4-carbaldehyde (100 mg, 0.568 mmol) was dissolved in DMF (2.8 ml). 3-(chloromethyl)-2-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl)pyridine hydrochloride (0.195 g, 0.625 mmol) and potassium carbonate (0.235 g, 1.7 mmol) were then added and the mixture was stirred in a 60° C. heat block for 16 h. The reaction mixture was cooled and water (50 ml) and ethyl acetate (100 ml) were added. The phases were separated and the aqueous phase was extracted with ethyl acetate (2×50 ml). The combined organic phases were washed with water (20 ml) and a saturated aqueous sodium chloride solution (20 ml). After drying over sodium sulfate and evaporation, the residue was purified by silica gel chromatography (5-50% ethyl acetate/hexanes) to give 86 mg (36%) of 3-(difluoromethyl)-1-methyl-5-((2-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-1H-pyrazole-4-carbaldehyde as an off-white solid. ¹H NMR (400 MHz, CDCl₃) δ 9.97 (s, 1H), 8.75 (d, J=3.64 Hz, 1H), 8.08 (d, J=7.31 Hz, 1H), 7.68 (d, J=1.69 Hz, 1H), 7.44 (dd, J=4.66, 7.83 Hz, 1H), 6.65 (t, J=53.67 Hz, 1H), 6.61 (d, J=1.78 Hz, 1H), 5.64 (s, 2H), 5.24 (q, J=8.60 Hz, 2H), 3.54 (s, 3H). MS (ESI) m/z 416 [M+H]⁺.

GBT986—1-methyl-5-((2-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-3-(trifluoromethyl)-1H-pyrazole-4-carbaldehyde

5-Hydroxy-1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-carbaldehyde (100 mg, 0.515 mmol) was dissolved in DMF (2.5 ml).). 3-(chloromethyl)-2-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl)pyridine hydrochloride (0.177 g, 0.567 mmol) and potassium carbonate (0.213 g, 1.545 mmol) were then added and the mixture was stirred in a 60° C. heat block for 16 h. The reaction mixture was cooled and water (50 ml) and ethyl acetate (100 ml) were added. The phases were separated and the aqueous phase was extracted with ethyl acetate (2×50 ml). The combined organic phases were washed with water (20 ml) and a saturated aqueous sodium chloride solution (20 ml). After drying over sodium sulfate and evaporation, the residue was purified by silica gel chromatography (5-50% ethyl acetate/hexanes) to give 86 mg (36%) of 1-methyl-5-((2-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-3-(trifluoromethyl)-1H-pyrazole-4-carbaldehyde as an off-white solid. ¹H NMR (400 MHz, CDCl₃) δ 9.87 (s, 1H), 8.75 (d, J=4.33 Hz, 1H), 8.08 (d, J=7.73 Hz, 1H), 7.68 (d, J=1.74 Hz, 1H), 7.45 (dd, J=4.64, 7.84 Hz, 1H), 6.59 (d, J=1.70 Hz, 1H), 5.63 (s, 2H), 5.24 (q, J=8.60 Hz, 2H), 3.57 (s, 3H). MS (ESI) m/z 434 [M+H]⁺.

GBT1065

GBT1065—4-fluoro-7-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-2,3-dihydro-1H-inden-1-one bis(2,2,2-trifluoroacetate). The compound was prepared by Mitsunobu reaction of of 4-fluoro-7-hydroxy-2,3-dihydro-1H-inden-1-one with [2-[1-(propan-2-yl)-1H-pyrazol-5-yl]pyridin-3-yl]methanol according to scheme 9, reaction step 3. The product TFA salt as white solid was obtained after HPLC purification. ¹HNMR (300 MHz, DMSO, ppm): 8.72 (m, 1H), 8.23 (m, 1H), 7.56 (m, 1H), 7.51 (d, J=1.8 Hz, 1H), 7.43 (m, 1H), 6.93 (m, 1H), 6.58 (d, J=1.8 Hz, 1H), 5.08 (s, 2H), 4.63 (m, 1H), 3.03 (m, 2H), 2.61 (m, 2H), 1.33 (d, J=6.6 Hz, 6H); MS (ES, m/z): 366[M+H]⁺

GBT1133—2-(((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)oxy)methyl)benzaldehyde. The compound was prepared from ethyl 2-(bromomethyl)benzonitrile in 2 steps according to reaction scheme below.

Step 1: Into a 100-mL round-bottom flask, was placed a solution of 2-(bromomethyl)benzonitrile (1.0 g, 3.10 mmol, 1.00 equiv) in dichloromethane (40 mL). This was followed by the addition of DIBAL-H (5.5 mL, 1.10 equiv) at 0° C. The resulting solution was stirred for 3.5 h at 0° C. The reaction was then quenched by the addition of 10 mL of 5% HBr at 0° C. The resulting solution was extracted with 3×30 mL of dichloromethane and the combined organic layers were dried over anhydrous sodium sulfate. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:10) as eluent. This resulted in 300 mg (49%) of 2-(bromomethyl)benzaldehyde as a green oil.

Step 2: Into a 50-mL round-bottom flask, was placed a solution of 2-(bromomethyl)benzaldehyde (130 mg, 0.73 mmol, 1.00 equiv) in CH₃CN (23 mL). 2-[1-(Propan-2-yl)-1H-pyrazol-5-yl]pyridin-3-ol (150 mg, 0.74 mmol, 1.00 equiv), potassium carbonate (210 mg, 1.52 mmol, 2.00 equiv), and KI (40 mg, 0.30 equiv) were added to the reaction. The resulting solution was heated to reflux for 6 h, and then it was cooled to rt. The resulting solution was diluted with 20 mL of H₂O, and then it was extracted with 3×20 mL of ethyl acetate. The combined organic layers were washed with 1×30 mL of brine and concentrated under vacuum. The crude product (200 mg) was purified by Prep-HPLC with the following conditions (Prep-HPLC-010): Column, SunFire Prep C18 OBD Column, 5 um, 19*150 mm; mobile phase, water with 0.05% TFA and MeCN (38.0% MeCN up to 55.0% in 8 min); Detector, nm. This provided 98.6 mg (41%) of 2-[([2-[1-(propan-2-yl)-1H-pyrazol-5-yl]pyridin-3-yl]oxy)methyl]benzaldehyde as a light yellow solid; ¹HNMR (300 MHz, CDCl₃, ppm): 10.01 (s, 1H), 8.43 (m, 1H), 7.88 (m, 1H), 7.86 (m, 1H), 7.61-7.79 (m, 6H), 6.61 (d, J=2.1 Hz, 1H), 5.60 (s, 2H), 4.69-4.78 (m, 1H), 1.46 (d, J=6.6 Hz, 6H); (ES, m/z): 322 [M+H]⁺

GBT1197—2-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde. The compound was prepared by O-alkylation of 2-hydroxybenzaldehyde with 3-(chloromethyl)-2-(1-isopropyl-1H-pyrazol-5-yl)pyridine (INT-4). The product of TFA salt as white solid was obtained after HPLC purification. ¹HNMR (300 MHz, CDCl₃, ppm): 10.49 (s, 1H), 8.78 (m, 1H), 8.16 (m, 1H), 7.88 (m, 1H), 7.69 (d, J=6.0 Hz, 1H), 7.54 (m, 2H), 7.13 (m, 1H), 6.90 (d, J=8.4 Hz, 1H), 6.41 (d, J=1.8 Hz, 1H), 5.11 (s, 2H), 4.62 (m, 1H); (ES, m/z): 322[M+H]⁺

GBT1252—2-((6-bromo-2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-6-hydroxybenzaldehyde. The compound was prepared by Mitsunobu reaction of (6-bromo-2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methanol (intermediate A) and 2,6-dihydroxybenzaldehyde (INT-3) according to scheme 9, reaction step 3. The product as white solid was obtained after flash column purification. ¹HNMR (300 MHz, DMSO, ppm): 11.70 (s, 1H), 11.20 (s, 1H), 8.17 (d, J=8.1 Hz, 1H), 7.81 (d, J=8.1 Hz, 1H), 7.57 (s, 1H), 7.50 (t, J=8.4 Hz, 1H), 6.60 (s, 1H), 6.55 (dd, J=8.4 Hz, 3.6 Hz, 1H), 5.19 (s, 2H), 4.65-4.55 (m, 1H), 1.38 (d, J=6.6 Hz, 6H); (ES, m/z:) 418.1 [M+H]⁺

Preparation of intermediate A. Intermediate A was prepared from 2,6-dichloropyridine-3-carboxylic acid in five steps according to the synthetic scheme below.

Step 1: Into a 500-mL round-bottom flask, was placed a solution of 2,6-dichloropyridine-3-carboxylic acid (25 g, 130.21 mmol, 1.00 equiv) in methanol (350 mL). This was followed by the addition of t-BuOK (43.8 g, 390.34 mmol, 3.00 equiv), in portions at 0° C. The resulting solution was heated to reflux for 3 days. The resulting mixture was concentrated under vacuum, and then it was diluted with 400 mL of water. The pH value of the solution was adjusted to 1 with hydrogen chloride aq. The solids were collected by filtration. The solid was dried in an oven under reduced pressure. This provided 20.5 g (84%) of 2-chloro-6-methoxypyridine-3-carboxylic acid as a white solid.

Step 2: Into a 100-mL round-bottom flask, was placed a solution of 2-chloro-6-methoxypyridine-3-carboxylic acid (11.3 g, 60.24 mmol, 1.00 equiv) in methanol (50 mL). This was followed by the addition of SOCl₂ (26 mL, 5.00 equiv) dropwise with stirring at 0° C. The resulting solution was stirred for 1 h at room temperature and for an additional 2 h at reflux. The resulting solution was diluted with 100 mL of water. The pH value of the solution was adjusted to 10 with 2M sodium carbonate aq. The resulting solution was extracted with 3×80 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 1×150 mL of water and 1×100 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:10) as eluent to furnish 7.8 g (64%) of methyl 2-chloro-6-methoxypyridine-3-carboxylate as a white solid.

Step 3: Into a 100-mL round-bottom flask, which was purged and maintained with an inert atmosphere of nitrogen, was placed methyl 2-chloro-6-methoxypyridine-3-carboxylate (3.29 g, 16.32 mmol, 1.00 equiv), 1-(propan-2-yl)-5-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (4.63 g, 19.61 mmol, 1.20 equiv), toluene (43 mL), ethanol (13 mL), sodium carbonate (2M in H₂O) (13 mL). This was followed by the addition of Pd(dppf)(DCM)Cl₂ (663 mg, 0.03 equiv). The resulting solution was stirred for 20 h at 90° C. The reaction was then quenched by the addition of 20 mL of water and 100 mL of ethyl acetate. The resulting mixture was washed with 2×30 mL of water and 1×30 mL of brine. The mixture was dried over anhydrous sodium sulfate. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:23-1:13) as eluent to furnish 3.83 g (83%) of methyl 6-methoxy-2-[1-(propan-2-yl)-1H-pyrazol-5-yl]pyridine-3-carboxylate as a light yellow oil.

-   -   Step 4: Into a 250-mL round-bottom flask, was placed methyl         6-methoxy-2-[1-(propan-2-yl)-1H-pyrazol-5-yl]pyridine-3-carboxylate         (3.6 g, 13.08 mmol, 1.00 equiv), C₆H₆ (60 mL), H₃PO₄ (85%) (150         mg, 1.53 mmol, 0.10 equiv), PyHBr (208 mg, 1.30 mmol, 0.10         equiv), POBr₃ (11.5 g, 40.11 mmol, 3.00 equiv). The resulting         solution was heated to reflux for 40 h. The reaction mixture was         cooled to 0° C. with an ice bath. The pH value of the solution         was adjusted to 10 with potassium carbonate sat. The resulting         solution was extracted with 3×80 mL of ethyl acetate and the         organic layers combined. The resulting mixture was washed with         2×30 mL of water and 1×30 mL of brine. The mixture was dried         over anhydrous sodium sulfate and concentrated under vacuum. The         residue was applied onto a silica gel column with ethyl         acetate/petroleum ether (1:10-1:8) as eluent. This provided 2.62         g (62%) of methyl         6-bromo-2-[1-(propan-2-yl)-1H-pyrazol-5-yl]pyridine-3-carboxylate         as a yellow oil.

Step 5: Into a 50-mL round-bottom flask, was placed methyl 6-bromo-2-[1-(propan-2-yl)-1H-pyrazol-5-yl]pyridine-3-carboxylate (2.62 g, 8.08 mmol, 1.00 equiv), tetrahydrofuran (30 mL). This was followed by the addition of LiBH₄ (330 mg, 16.07 mmol, 2.00 equiv) at 0° C. The resulting solution was stirred for 30 min at 0° C. and for an additional 1 h at room temperature. The reaction mixture was cooled to 0° C. with an ice bath. The reaction was then quenched by the addition of 20 mL of water. The resulting solution was extracted with 3×60 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 2×30 mL of water and 1×30 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:8-1:5) as eluent to furnish 1.97 g (82%) of [6-bromo-2-[1-(propan-2-yl)-1H-pyrazol-5-yl]pyridin-3-yl]methanol as a light yellow solid.

GBT933—4-(dimethylamino)-2-hydroxy-6-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde

Step 1: Into a 250-mL round-bottom flask, was placed a solution of 3,5-dimethoxyaniline (1) (4.6 g, 30.03 mmol, 1.00 equiv) and potassium carbonate (14.6 g, 105.64 mmol, 4.00 equiv) in N,N-dimethylformamide (80 mL). This was followed by the addition of SO₂(OMe)₂ (8.4 g, 66.67 mmol, 2.00 equiv) dropwise with stirring at 0° C. The mixture was stirred for 2 h at 0° C. The resulting solution was stirred overnight at room temperature, and then it was quenched by the addition of 100 mL of water. The resulting solution was extracted with 2×80 mL of ethyl acetate. The combined organic layers were washed with 1×50 mL of water and 1×50 mL of brine, dried over anhydrous sodium sulfate. The residue was applied onto a silica gel column with PE:EA (30:1-10:1) as eluent to furnish 2.8 g (51%) of 3,5-dimethoxy-N,N-dimethylaniline (2) as a white solid.

Step 2: Into a 50-mL round-bottom flask, was placed a solution of 3,5-dimethoxy-N,N-dimethylaniline (2) (2.4 g, 13.24 mmol, 1.00 equiv) in N,N-dimethylformamide (25 mL). This was followed by the addition of POCl₃ (2.57 g, 16.76 mmol, 1.30 equiv) dropwise with stirring at 0° C. The resulting solution was stirred for 15 min at 0° C., and then it was quenched by the addition of 100 mL of sodium hydroxide (aq). The pH value of the solution was adjusted to 12 with sodium hydroxide (aq). The resulting solution was extracted with 3×60 mL of ethyl acetate. The combined organic layers were washed with 1×60 mL of water and 1×60 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:1-1:0) as eluent to yield 2.08 g (73%) of 4-(dimethylamino)-2,6-dimethoxybenzaldehyde (3) as a white solid.

Step 3: Into a 50-mL round-bottom flask, was placed a solution of 4-(dimethylamino)-2,6-dimethoxybenzaldehyde (3) (630 mg, 3.01 mmol, 1.00 equiv) in dichloromethane (23 mL). AlCl₃ (6 g, 43.11 mmol, 12.30 equiv) was added to the reaction. The resulting solution was heated to reflux for 24 h. The pH value of the solution was adjusted to 8-9 with sodium bicarbonate (aq). The resulting solution was extracted with 3×80 mL of ethyl acetate. The combined organic layers were washed with 1×60 mL of water and 1×60 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:4) as eluent to furnish 383 mg (70%) of 4-(dimethylamino)-2,6-dihydroxybenzaldehyde (4) as a light yellow solid.

Step 4: Into a 23-mL round-bottom flask, was placed a solution of [2-[1-(propan-2-yl)-1H-pyrazol-5-yl]pyridin-3-yl]methanol (5) (132 mg, 0.61 mmol, 1.00 equiv), 4-(dimethylamino)-2,6-dihydroxybenzaldehyde (4) (110 mg, 0.61 mmol, 1.00 equiv), PPh₃ (207.3 mg, 0.79 mmol, 1.30 equiv) in tetrahydrofuran (10 mL). DIAD (160 mg, 0.79 mmol, 1.30 equiv) was added to the reaction dropwise dropwise at 0° C. The resulting solution was stirred for 10 min at 0° C. and for an additional 2 h at room temperature. The reaction was then quenched with 10 mL of water. The resulting solution was extracted with 3×40 mL of ethyl acetate. The combined organic layers were washed with 3×20 mL of water and 1×20 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by Prep-HPLC with the following conditions (Prep-HPLC-010): Column, SunFire Prep C18 OBD Column, 5 um, 19*130 mm; mobile phase, water with 0.05% TFA and MeCN (30.0% MeCN up to 60.0% in 10 min, up to 95.0% in 4 min, down to 30.0% in 2 min); Detector, Waters2545 UvDector 254&220 nm. This resulted in 60 mg (26%) of 4-(dimethylamino)-2-hydroxy-6-([2-[1-(propan-2-yl)-1H-pyrazol-5-yl]pyridin-3-yl]methoxy)benzaldehyde (GBT933) as a light yellow solid.

¹HNMR (400 MHz, CDCl₃, ppm): 12.45 (br s, 1H), 9.87 (s, 1H), 8.70 (d, J=4.0 Hz, 1H), 7.96 (d, J=7.2 Hz, 1H), 7.58 (s, 1H), 7.42-7.39 (m, 1H), 6.32 (s, 1H), 5.68 (s, 1H), 5.43 (s, 1H), 4.94 (s, 2H), 4.58-4.51 (m, 1H), 2.96 (s, 6H), 1.40 (d, J=6.8 Hz, 1H); MS (ES, m/z:) 381.2 [M−2CF₃COOH+1]⁺

GBT953—(S)-2-hydroxy-6-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde

Step 1: Into a 250-mL round-bottom flask, was placed a solution of methyl 3-hydroxybenzoate (3 g, 19.72 mmol, 1.00 equiv) in trifluoroacetic acid (100 mL). Urotropin (5.5 g, 39.29 mmol, 2.00 equiv) was added to the reaction. The resulting solution was heated to reflux for 2 hr. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:5) as eluent to furnish 0.5 g (14%) of methyl 2-formyl-3-hydroxybenzoate as a yellow solid.

Step 2: Into a 100-mL round-bottom flask, was placed a solution of methyl 2-formyl-3-hydroxybenzoate (400 mg, 2.22 mmol, 1.00 equiv) in CH3CN (30 mL). 3-(Chloromethyl)-2-[1-(propan-2-yl)-1H-pyrazol-5-yl]pyridine (523 mg, 2.22 mmol, 1.00 equiv), potassium carbonate (927 mg, 6.71 mmol, 3.00 equiv), and KI (40 mg, 0.24 mmol, 0.10 equiv) were added to the reaction. The resulting solution was stirred for 2 h at 60° C., and then it was diluted with 200 ml of EA. The resulting mixture was washed with 2×100 mL of brine, and then it was concentrated under vacuum. This provided 500 mg (59%) of methyl 2-formyl-3-([2-[1-(propan-2-yl)-1H-pyrazol-5-yl]pyridin-3-yl]methoxy)benzoate as a yellow oil.

Step 3: Into a 100-mL round-bottom flask, was placed a solution of methyl 2-formyl-3-([2-[1-(propan-2-yl)-1H-pyrazol-5-yl]pyridin-3-yl]methoxy)benzoate (100 mg, 0.26 mmol, 1.00 equiv) in tetrahydrofuran (10 mL). This was followed by the addition of a solution of sodium hydroxide (22 mg, 0.55 mmol, 2.00 equiv) in water (3 mL) dropwise with stirring at 0° C. The resulting solution was stirred for 3 h at room temperature. The pH value of the solution was adjusted to 6 with hydrogen chloride (3 mol/L). The resulting solution was extracted with 2×100 mL of ethyl acetate and the organic layers combined and concentrated under vacuum. The crude product (100 mg) was purified by Prep-HPLC with the following conditions (Prep-HPLC-010): Column, SunFire Prep C18 OBD Column, 5 um, 19*150 mm; mobile phase, water with 0.05% TFA and MeCN (30% MeCN up to 60% in 10 min, up to 95% in 3 min, down to 30% in 2 min); Detector, Waters2545 UvDector 254&220 nm. This resulted in 30 mg (19%) of 2-formyl-3-([2-[1-(propan-2-yl)-1H-pyrazol-5-yl]pyridin-3-yl]methoxy)benzoic acid; bis(trifluoroacetic acid) as a white solid. ¹HNMR (300 MHz, DMSO, ppm): 8.75 (dd, J=4.8 Hz, 1H), 8.15 (m, 2H), 7.59 (m, 3H), 7.40 (d, J=7.8 Hz, 1H), 7.33 (d, J=8.1 Hz, 1H), 6.66 ((d, J=7.8 Hz, 1H), 6.60 (s, 1H), 5.18 (m, 2H), 4.70 (m, 1H), 1.35 (m, 6H); MS (ES, m/z):366 [M+1]+

GBT963—(S)-2-hydroxy-6-((5-oxo-1-phenylpyrrolidin-2-yl)methoxy)benzaldehyde

Step 1: To a suspension of (S)-5-(hydroxymethyl)pyrrolidin-2-one (230 mg, 2 mmol) and iodobenzene (0.49 g, 2.4 mmol) in Dioxane (4 mL) was added CuI (0.08 g, 0.4 mmol), N,N-dimethylethylenediamine (0.05 mL, 0.4 mmol), K₂CO₃ (0.55 g, 4 mmol). After heating at 100° C. for 24 h, the mixture was cooled and was diluted with EtOAc, insoluble material was filtered off, the filtrate was concentrated and purified by column (Hexanes/EtOAc=100:0 to 0:100) to give (S)-5-(hydroxymethyl)-1-phenylpyrrolidin-2-one (280 mg).

Step 2: To a solution of (S)-5-(hydroxymethyl)-1-phenylpyrrolidin-2-one (100 mg, 0.52 mmol) and 2,6-dihydroxybenzaldehyde (0.09 g, 0.65 mmol) in THF (5 mL) at 0° C. was added PPh₃ (polymer supported, 650 mg, 0.78 mmol) and DIAD (0.16 mL, 0.78 mmol). After stirred for 1 h, it was diluted with AcCN, the insoluble material was filtered off and the filtrate was concentrated and purified by preparative HPLC to give (S)-2-hydroxy-6-((5-oxo-1-phenylpyrrolidin-2-yl)methoxy)benzaldehyde (86 mg). ¹H NMR (400 MHz, Chloroform-d) δ 11.91 (d, J=0.4 Hz, 1H), 9.93 (d, J=0.6 Hz, 1H), 7.50-7.18 (m, 6H), 6.53 (dt, J=8.5, 0.7 Hz, 1H), 6.21 (dd, J=8.3, 0.8 Hz, 1H), 4.70-4.59 (m, 1H), 4.15-4.01 (m, 2H), 2.82-2.58 (m, 2H), 2.50 (ddt, J=13.1, 9.9, 8.3 Hz, 1H), 2.16 (dddd, J=13.6, 9.5, 5.1, 3.9 Hz, 1H). MS found for C₁₈H₁₇NO₄: 312.3.

GBT998—(S)-2-hydroxy-6-((5-oxo-1-phenylpyrrolidin-2-yl)methoxy)benzaldehyde

Step 1: To a suspension of (S)-5-(hydroxymethyl)pyrrolidin-2-one (230 mg, 2 mmol) and 1-iodo-2-methoxybenzene (0.56 g, 2.4 mmol) in Dioxane (4 mL) was added CuI (0.08 g, 0.4 mmol), N,N-dimethylethylenediamine (0.05 mL, 0.4 mmol), K₃PO₄ (0.85 g, 4 mmol). After heating at 100° C. for 24 h, the mixture was cooled and was diluted with EtOAc, insoluble material was filtered off, the filtrate was concentrated and purified by column (Hexanes/EtOAc=100:0 to 0:100) to give (S)-5-(hydroxymethyl)-1-(2-methoxyphenyl)pyrrolidin-2-one (110 mg).

Step 2: To a solution of (S)-5-(hydroxymethyl)-1-phenylpyrrolidin-2-one (115 mg, 0.54 mmol) and 2,6-dihydroxybenzaldehyde (0.10 g, 0.70 mmol) in THF (4 mL) at 0° C. was added PPh₃ (polymer supported, 675 mg, 0.81 mmol) and DIAD (0.16 mL, 0.81 mmol). After stirred for 1 h, it was diluted with AcCN, the insoluble material was filtered off and the filtrate was concentrated and purified by column (100% EtOAc) to give (S)-2-hydroxy-6-((1-(2-methoxyphenyl)-5-oxopyrrolidin-2-yl)methoxy)benzaldehyde (53 mg). ¹H NMR (400 MHz, Chloroform-d) δ 11.92 (s, 1H), 9.68 (t, J=0.5 Hz, 1H), 7.38-7.30 (m, 1H), 7.30-7.22 (m, 1H), 7.14 (dd, J=7.7, 1.7 Hz, 1H), 6.99-6.89 (m, 2H), 6.50 (dq, J=8.5, 0.6 Hz, 1H), 6.25-6.18 (m, 1H), 4.55 (dtd, J=9.0, 5.1, 4.0 Hz, 1H), 4.10-3.94 (m, 2H), 3.73 (s, 3H), 2.75-2.55 (m, 2H), 2.48 (dddd, J=13.0, 9.6, 8.4, 7.3 Hz, 1H), 2.16-2.02 (m, 1H). MS found for C₁₉H₁₉NO₅: 342.3.

GBT1004—2-amino-4-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy) nicotinaldehyde

Step 1: Into a 250-mL round-bottom flask, was placed a solution of 4-chloropyridin-2-amine (10 g, 77.78 mmol, 1.00 equiv) in tetrahydrofuran (150 mL). This was followed by the addition of LiHMDS(1M) (156 mL) dropwise with stirring at 0° C. The mixture was stirred for 20 min at 0° C. To this was added Boc₂O (17.02 g, 77.98 mmol, 1.00 equiv). The resulting solution was stirred for 1 h at 0° C. The reaction was then quenched by the addition of 100 mL of NH₄Cl. The resulting solution was extracted with 2×200 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 1×150 mL of brine. The resulting mixture was concentrated under vacuum, washed with 2×20 mL of EA/hexane (3:7). This resulted in 12.5 g (70%) of tert-butyl N-(4-chloropyridin-2-yl)carbamate as a white solid.

Step 2: Into a 100-mL three neck round-bottom flask, was placed a solution of tert-butyl N-(4-chloropyridin-2-yl)carbamate (2 g, 8.75 mmol, 1.00 equiv) in tetrahydrofuran (50 mL). This was followed by the addition of BuLi (2.5M) (7.0 mL, 2.00 equiv) dropwise with stirring at −78° C. in 20 min. The mixture was stirred for 0.5 h at −78° C. To this was added N,N-dimethylformamide (2.0 mL, 3.00 equiv) dropwise with stirring at −78° C. in 5 min. The resulting solution was stirred for 1 h at −78° C. The reaction was then quenched by the addition of 3 mL of hydrogen chloride (12M). The resulting mixture was concentrated under vacuum. The resulting solution was diluted with 50 mL of ethyl acetate. The resulting mixture was washed with 1×40 mL of 5% sodium bicarbonate and 1×30 mL of brine. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with EA:PE (1:4). This resulted in 1.46 g (65%) of tert-butyl N-(4-chloro-3-formylpyridin-2-yl)carbamate as a yellow solid.

Step 3: Into a 100-mL round-bottom flask, was placed a solution of [2-[1-(propan-2-yl)-1H-pyrazol-5-yl]pyridin-3-yl]methanol (500 mg, 2.30 mmol, 1.20 equiv) in N,N-dimethylformamide (50 mL). This was followed by the addition of sodium hydride (190 mg, 7.92 mmol, 2.50 equiv) at 0° C. The mixture was stirred for 20 min at 0° C. To this was added tert-butyl N-(4-chloro-3-formylpyridin-2-yl)carbamate (500 mg, 1.95 mmol, 1.00 equiv). The resulting solution was stirred overnight at room temperature, and then it was quenched by the addition of 50 mL of water. The resulting solution was extracted with 8×20 mL of ethyl acetate and the organic layers combined and concentrated under vacuum. This resulted in 506 mg (59%) of tert-butyl N-[3-formyl-4-([2-[1-(propan-2-yl)-1H-pyrazol-5-yl]pyridin-3-yl]methoxy)pyridin-2-yl]carbamate as a yellow oil.

Step 4: Into a 100-mL round-bottom flask, was placed a solution of trifluoroacetic acid (10 mL) in dichloromethane (60 mL), tert-butyl N-[3-formyl-4-([2-[1-(propan-2-yl)-1H-pyrazol-5-yl]pyridin-3-yl]methoxy)pyridin-2-yl]carbamate (500 mg, 1.14 mmol, 1.00 equiv). The resulting solution was stirred overnight at room temperature. The resulting mixture was concentrated under vacuum. The crude product (500 mg) was purified by Prep-HPLC with the following conditions (Prep-HPLC-010): Column, SunFire Prep C18 OBD Column, 5 um, 19*150 mm; mobile phase, water with 0.05% TFA and MeCN (5.0% MeCN up to 26.0% in 10 min, up to 95.0% in 2 min, down to 5.0% in 2 min); Detector, Waters2545 UvDector 254&220 nm. This resulted in 122.9 mg (32%) of 2-amino-4-([2-[1-(propan-2-yl)-1H-pyrazol-5-yl]pyridin-3-yl]methoxy)pyridine-3-carbaldehyde as a yellow solid. ¹HNMR (300 MHz, DMSO, ppm): 10.12 (s, 1H), 8.79 (m, 1H), 8.24 (m, 2H), 7.59 (m, 2H), 6.76 (d, J=5.1 Hz, 1H), 6.55 (d, J=1.2 Hz, 1H), 5.43 (m, 2H), 4.67 (m, 1H), 1.36 (m, 6H); MS (ES, m/z): 338 [M+1−3CF₃COOH]⁺

GBT1006—4-((2-(1-isopropyl-1H-pyrazol-5-yl)pyrrolin-3-yl)methoxy)-2-(methylamino)nicotinaldehyde

Step 1: Into a 100-mL round-bottom flask, was placed a solution of tert-butyl N-(4-chloropyridin-2-yl)carbamate (3.0 g, 13.12 mmol, 1.00 equiv) in tetrahydrofuran (50 mL). This was followed by the addition of sodium hydride (631 mg, 26.29 mmol, 1.20 equiv) at 0° C. The mixture was stirred for 20 min at 0° C. To this was added iodomethane (2.24 g, 15.78 mmol, 1.20 equiv) dropwise with stirring. The resulting solution was stirred for 6 h at room temperature. The reaction was then quenched by the addition of 30 mL of water. The resulting solution was extracted with 3×30 mL of ethyl acetate and the organic layers combined and concentrated under vacuum. This resulted in 3.01 g (95%) of tert-butyl N-(4-chloropyridin-2-yl)-N-methylcarbamate as a yellow oil.

-   -   Step 2: Into a 100-mL three neck round-bottom flask, was placed         a solution of tert-butyl         N-(4-chloropyridin-2-yl)-N-methylcarbamate (1.5 g, 6.18 mmol,         1.00 equiv) in tetrahydrofuran (50 mL). This was followed by the         addition of BuLi (2.5M) (3.0 mL, 1.20 equiv) dropwise with         stirring at −78° C. The mixture was stirred for 30 mins at         −78° C. To this was added N,N-dimethylformamide (1.5 mL, 3.00         equiv) dropwise with stirring at −78° C. The resulting solution         was stirred for 1 h at −78° C. The reaction was then quenched by         the addition of 2.5 mL of hydrogen chloride (12M). The resulting         mixture was concentrated under vacuum. The residue was dissolved         in 40 mL of EA. The resulting mixture was washed with 1×30 mL of         5% sodium bicarbonate and 1×20 mL of brine. The resulting         mixture was concentrated under vacuum. The residue was applied         onto a silica gel column with EA:PE (1:4). This resulted in 0.97         g (92%) of 4-chloro-2-(methylamino)pyridine-3-carbaldehyde as a         yellow solid.

Steps 3 &4: Into a 100-mL round-bottom flask, was placed a solution of [2-[1-(propan-2-yl)-1H-pyrazol-5-yl]pyridin-3-yl]methanol (1.15 g, 5.29 mmol, 1.00 equiv) in N,N-dimethylformamide (40 mL). This was followed by the addition of sodium hydride (530 mg, 13.25 mmol, 2.50 equiv, 60%) at 0° C. The mixture was stirred for 15 min at 0° C. To this was added 4-chloro-2-(methylamino)pyridine-3-carbaldehyde (900 mg, 5.28 mmol, 1.00 equiv). The resulting solution was stirred overnight at room temperature. The reaction was then quenched by the addition of 30 mL of water. The resulting solution was extracted with 5×30 mL of ethyl acetate and the organic layers combined and concentrated under vacuum. The crude product (300 mg) was purified by Prep-HPLC with the following conditions (Prep-HPLC-020): Column, SunFire Prep C18 OBD Column, 5 um, 19*100 mm; mobile phase, water with 0.1% TFA and MeCN (3.0% MeCN up to 20.0% in 5 min, up to 95.0% in 2 min, down to 3.0% in 1 min); Detector, waters 2489 254&220 nm. This resulted in 107.1 mg (6%) of 2-(methylamino)-4-([2-[1-(propan-2-yl)-1H-pyrazol-5-yl]pyridin-3-yl]methoxy)pyridine-3-carbaldehyde as a yellow solid. ¹HNMR (400 MHz, DMSO, ppm): 8.72 (m, 1H), 8.17 (s, 1H), 7.91 (m, 1H), 7.52 (m, 3H), 6.56 (s, 1H), 6.26 (d, J=4.2 Hz, 1H), 6.15 (d, J=3.3 Hz, 1H), 5.43 (m, 1H), 5.12 (m, 1H), 4.60 (m, 1H), 2.87 (d, J=3.3 Hz, 1H), 1.46 (d, J=5.1 Hz, 1H), 1.35 (d, J=5.1 Hz, 1H); (ES, m/z):352.1 [M+1]⁺

GBT1007—2-(4-(hydroxymethyl)-1,3-dioxolan-2-yl)-3-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)phenol

2-Hydroxy-6-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde (0.4 g, 1.19 mmol) was dissolved in a solution of propane-1,2,3-triol (5.8 ml, 79 mmol) and DMF (5 ml). Amberlyst 15 resin (80 mg) and 3A molecular sieves (1 g) were added and the mixture was stirred in a heat block at 70° C. for 18 h. After cooling the mixture was filtered and taken up in ethyl acetate (200 ml) and water (100 ml). The phases were separated and the aqueous phase was extracted with ethyl acetate (2×50 ml). The combined organic phases were washed with water (50 ml) and a saturated aqueous sodium chloride solution (50 ml), and dried over sodium sulfate. After evaporation, the residue was purified by silica gel chromatography (0-90% ethyl acetate/dichloromethane) to give 0.118 g (24%) of 2-(4-(hydroxymethyl)-1,3-dioxolan-2-yl)-3-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)phenol as an off-white solid after lyophilization from acetonitrile/water. ¹H NMR (400 MHz, CDCl₃) δ 8.74-8.67 (m, 1H), 8.53 (s, 0.6H), 8.18-8.12 (m, 0.4H), 7.97 (d, J=7.90 Hz, 1H), 7.62-7.55 (m, 1H), 7.44-7.34 (m, 1H), 7.17-7.07 (m, 1H), 6.55 (d, J=8.47 Hz, 1H), 6.42-6.36 (m, 1H), 6.31-6.23 (m, 1.6H), 5.95-5.89 (m, 0.4H), 4.98 (s, 2H), 4.71-4.58 (m, 1H), 4.40-4.28 (m, 1.5H), 4.24-4.17 (m, 0.6H), 4.10-4.01 (m, 1H), 3.99-3.92 (m, 0.6H), 3.73-3.65 (m, 0.6H), 3.56 (dd, J=10.09, 20.18 Hz, 1H), 1.51-1.43 (m, 6H). MS (ESI) m/z 412 [M+H]⁺.

GBT1090—(S)-2-((1-benzyl-5-oxopyrrolidin-2-yl)methoxy)-6-hydroxybenzaldehyde

Step 1: To a solution of (S)-methyl 5-oxopyrrolidine-2-carboxylate (700 mg, 4.89 mmol) in DMF (5 mL) was added Cs₂CO₃ (1.97 g, 5.99 mmol) and BnBr (0.59 mL, 4.99 mmol). After heated at 60° C. for 15 h, it was diluted with EtOAc, organic layer was washed with water, brine, dried and concentrated to give crude product which was purified by column (Hexanes/EtOAc=40:60) to give methyl (S)-1-benzyl-5-oxopyrrolidine-2-carboxylate (240 mg). To a solution of methyl (S)-1-benzyl-5-oxopyrrolidine-2-carboxylate (240 mg, 1.0 mmol) in THF (2 mL) was added LiBH₄ (1M in THF, 1 mL, 1 mmol) at room temperature. After stirred at room temperature for 1 h, the solution was quenched with Sat. NH₄Cl, aqueous layer was extracted with EtOAc, EtOAc layer was combined, dried and concentrated to give crude product, which was purified by column (100% EtOAc) to give (S)-1-benzyl-5-(hydroxymethyl)pyrrolidin-2-one (170 mg).

Step 2: To a solution of (S)-1-benzyl-5-(hydroxymethyl)pyrrolidin-2-one (170 mg, 0.83 mmol) and 2,6-dihydroxybenzaldehyde (0.15 g, 1.08 mmol) in THF (6 mL) was added PPh₃ (polymer supported, 1.0 g, 1.25 mmol) and DIAD (0.24 mL, 1.25 mmol) at 0° C. Then it was warmed up to room temperature and stirred for 1 h, AcCN was added to dilute the mixture, the insoluble material was filtered off, the filtrate was concentrated and was purified by preparative HPLC to give (S)-2-((1-benzyl-5-oxopyrrolidin-2-yl)methoxy)-6-hydroxybenzaldehyde (95 mg). ¹H NMR (400 MHz, Chloroform-d) δ 11.93 (t, J=0.4 Hz, 1H), 10.17 (t, J=0.5 Hz, 1H), 7.39-7.29 (m, 1H), 7.29-7.18 (m, 5H), 6.54 (dt, J=8.5, 0.7 Hz, 1H), 6.17 (dd, J=8.3, 0.9 Hz, 1H), 4.85 (d, J=15.2 Hz, 1H), 4.28 (d, J=15.2 Hz, 1H), 3.99 (d, J=4.0 Hz, 2H), 3.92 (td, J=7.8, 7.2, 3.6 Hz, 1H), 2.68-2.45 (m, 2H), 2.33-2.19 (m, 1H), 2.10-1.96 (m, 1H). MS (M+H) found for C₁₉H₁₉NO₄: 326.4.

GBT1093—(S)-2-hydroxy-6-((5-oxo-4-phenylmorpholin-3-yl)methoxy)benzaldehyde

Step 1: To a solution of (S)-benzyl 2-amino-3-hydroxypropanoate hydrochloride (5 g, 21.58 mmol) in THF-water (1/1, 80 mL) was added K₂CO₃ (8.95 g, 64.74 mmol) and chloroacetyl chloride (2.92 mL, 36.69 mmol). After stirred for 1 h, it was diluted with EtOAc, organic layer was washed with water, brine, dried and concentrated to give benzyl (2-chloroacetyl)-L-serinate (5 g).

Step 2: A solution of (S)-benzyl 2-(2-chloroacetamido)-3-hydroxypropanoate (2.55 g, 9.39 mmol) in iPrOH (20 mL) was added to KOtBu (3.16 g, 28.17 mmol) in iPrOH (15 mL) at room temperature. After stirred at room temperature for 1 h, the mixture was quenched with 6N HCl (10 mL) at 0° C., extracted with EtOAc, organic layers were combined, washed with brine, dried and concentrated to give isopropyl (2-chloroacetyl)-L-serinate as crude product.

Step 3: To a solution of (S)-benzyl 5-oxomorpholine-3-carboxylate in EtOH (7 mL) was added NaBH₄ (150 mg) at 0° C., after stirred at room temperature for 3 h, it was quenched with NH₄Cl (220 mg in 0.6 mL water), and the insoluble material was filtered off, the filtrate was concentrated and was purified by column (DCM/MeOH=100:0 to 80:20) to give (R)-5-(hydroxymethyl)morpholin-3-one (100 mg).

Step 4: To a suspension of (R)-5-(hydroxymethyl)morpholin-3-one (100 mg, 2 mmol) and 3-iodopyridine (0.57 g, 2.8 mmol) in Dioxane (4 mL) was added CuI (0.08 g, 0.4 mmol), N,N-dimethylethylenediamine (0.05 mL, 0.4 mmol), K₃PO₄ (0.85 g, 4 mmol). After heating at 100° C. for 24 h, the mixture was cooled and was diluted with EtOAc, insoluble material was filtered off, the filtrate was concentrated and purified by column (Hexanes/EtOAc=100:0 to 0:100) to give (S)-5-(hydroxymethyl)-1-(pyridin-3-yl)pyrrolidin-2-one (55 mg).

Step 5: To a solution of (S)-5-(hydroxymethyl)-1-(pyridin-3-yl)pyrrolidin-2-one (55 mg, 0.29 mmol) and 2,6-dihydroxybenzaldehyde (0.05 g, 0.38 mmol) in THF (2 mL) was added PPh₃ (polymer supported, 367 mg, 0.44 mmol) and DIAD (0.09 mL, 0.44 mmol) at 0° C. Then it was warmed up to room temperature and stirred for 1 h, AcCN was added to dilute the mixture, the insoluble material was filtered off, the filtrate was concentrated and was purified by preparative HPLC to give (S)-2-hydroxy-6-((5-oxo-4-phenylmorpholin-3-yl)methoxy)benzaldehyde (29 mg). ¹H NMR (400 MHz, Chloroform-d) δ 11.88 (d, J=0.4 Hz, 1H), 9.94 (d, J=0.6 Hz, 1H), 7.53-7.40 (m, 2H), 7.40-7.30 (m, 2H), 7.26 (s, 2H), 6.53 (dt, J=8.5, 0.7 Hz, 1H), 6.20 (dd, J=8.3, 0.8 Hz, 1H), 4.47 (dd, J=16.9, 0.9 Hz, 1H), 4.40-4.25 (m, 3H), 4.25-4.16 (m, 1H), 4.15-4.07 (m, 2H). MS (M+H) found for C₁₈H₁₇NO₅: 328.3.

GBT1123—tert-butyl (2-formyl-3-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)phenyl)carbamate

Step 1: tert-Butyl (3-methoxyphenyl)carbamate (0.517 g, 2.3 mmol) was dissolved in dry diethyl ether (12 ml) and cooled to −40° C. in a solvent bath. t-Butyl lithium (4.1 ml of a 1.7 M pentane solution, 6.95 mmol) was added dropwise, the reaction was allowed to warm to −20° C. and stirred for 2 h more. The reaction was cooled to ˜−78° C., DMF (0.54 ml, 6.95 mmol) was added, and the reaction was allowed to gradually warm to 25° C. over 16 h. The reaction mixture was cooled in an ice bath and ammonium chloride solution (10 ml) was added. The reaction was extracted with ethyl acetate (3×80 ml), the combined organic phases were washed with a saturated aqueous sodium chloride solution (50 ml) and dried over sodium sulfate. After evaporation, the residue was purified by silica gel chromatography (0-30% ethyl acetate/hexanes) to give 0.46 g (79%) of tert-butyl (2-formyl-3-methoxyphenyl)carbamate as a lightly-colored solid. MS (ESI) m/z 252 [M+H]⁺.

Step 2: tert-Butyl (2-formyl-3-methoxyphenyl)carbamate (0.38 g, 1.5 mmol) was dissolved in dichloromethane (10 ml) and added dropwise to a solution of aluminum chloride (1 g, 7.56 mmol) in dichloromethane (15 ml) while stirring in an ice bath. The yellowish solution was then stirred in a heat block at 50° C. After 4 h, ice and water were added and the mixture stirred for 15 m. The reaction mixture was extracted with dichloromethane (3×50 ml), the combined organic phases were washed with water (30 ml) and a saturated aqueous sodium chloride solution (30 ml), and dried over sodium sulfate. After evaporation the crude residue was carried directly into the next step. MS (ESI) m/z 138 [M+H]⁺.

Step 3: 2-Amino-6-hydroxybenzaldehyde (0.207 g, 1.5 mmol) was dissolved in THF (4 ml). Di-tert-butyldicarbonate (0.726 g, 3.3 mmol) and 4-dimethylaminopyridine (37 mg, 0.3 mmol) were added and the reaction was stirred for 18 h. The solution was evaporated and the residue was purified by silica gel chromatography (0-40% ethyl acetate/hexanes) to give 50 mg (14%) of tert-butyl (2-formyl-3-hydroxyphenyl)carbamate. MS (ESI) m/z 238 [M+H]⁺.

Step 4: tert-Butyl (2-formyl-3-hydroxyphenyl)carbamate (50 mg, 0.21 mmol) and 3-(chloromethyl)-2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-1-ium chloride (57 mg, 0.21 mmol) were dissolved in DMF (3 ml). The solution was purged with Ar gas. Potassium carbonate (116 mg 0.84 mmol) was added and the reaction mixture was stirred in a 60° C. heat block for 18 h. The reaction was cooled and water (50 ml) and ethyl acetate (50 ml) were added. The phases were separated and the aqueous phase was extracted with ethyl acetate (2×50 ml). The combined organic phases were washed with a saturated aqueous sodium chloride solution and dried over sodium sulfate. After evaporation the residue was purified by silica gel chromatography (5-50% ethyl acetate/hexanes) to give 5 mg (5%) of tert-butyl (2-formyl-3-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)phenyl)carbamate as a white solid after lyophilization from acetonitrile/water. ¹H NMR (400 MHz, CDCl₃) δ 10.51 (s, 1H), 8.74 (d, J=4.81 Hz, 1H), 8.06 (d, J=7.84 Hz, 1H), 7.60 (s, 1H), 7.48 (t, J=8.22 Hz, 1H), 7.44-7.39 (m, 1H), 6.91-6.81 (m, 2H), 6.36 (s, 1H), 5.10 (s, 2H), 4.64 (d, J=6.51 Hz, 1H), 1.47 (d, J=4.57 Hz, 6H), 1.41 (s, 9H). MS (ESI) m/z 437 [M+H]⁺.

GBT1131—(S)-2-hydroxy-6-((6-oxo-1-phenylpiperidin-2-yl)methoxy)benzaldehyde

Step 1: To a suspension of (S)-6-oxopiperidine-2-carboxylic acid (1.0 g, 6.99 mmol) in EtOH (4 mL) at 0° C. was added SOCl₂ (0.61 mL, 8.39 mmol). After stirred at room temperature for 3 h, it was concentrated to remove all solvents, dried under high vacuum to give corresponding ethyl ester. The ester was dissolved in EtOH (15 mL) and was added NaBH₄ (300 mg) at 0° C., the mixture was warmed up to room temperature and stirred for additional 15 h. The mixture was quenched with Sat. NH₄Cl, filtered off the insolubles and the filtrate was concentrated to give crude product, which was purified by column (DCM/MeOH=90:10) to give (S)-6-(hydroxymethyl)piperidin-2-one (450 mg) as white solid.

Step 2: To a suspension of (S)-6-(hydroxymethyl)piperidin-2-one (150 mg, 1.16 mmol) and iodobenzene (0.35 g, 1.74 mmol) in Dioxane (2 mL) was added CuI (0.09 g, 0.46 mmol), N,N-dimethylethylenediamine (0.04 mL, 0.35 mmol), K₃PO₄ (0.49 g, 2.32 mmol). After heating at 100° C. for 24 h, the mixture was cooled and was diluted with EtOAc, organic layer was washed with brine, dried (Na₂SO₄) and concentrated to give crude product, which was purified by column (Hexanes/EtOAc=100:0 to 0:100) to give (S)-6-(hydroxymethyl)-1-phenylpiperidin-2-one (85 mg).

Step 3: To a solution of (S)-6-(hydroxymethyl)-1-phenylpiperidin-2-one (85 mg, 0.44 mmol) and 2,6-dihydroxybenzaldehyde (0.08 g, 0.57 mmol) in THF (5 mL) was added PPh3 (polymer supported, 550 mg, 0.66 mmol) and DIAD (0.13 mL, 0.66 mmol) at 0° C. After warmed to room temperature and further stirred for 2 h, it was diluted with AcCN, the insoluble material was filtered off and the filtrate was concentrated and subjected to preparative HPLC to give (S)-2-hydroxy-6-((6-oxo-1-phenylpiperidin-2-yl)methoxy)benzaldehyde (31 mg). ¹H NMR (400 MHz, Chloroform-d) δ 11.90 (d, J=0.4 Hz, 1H), 10.08 (d, J=0.6 Hz, 1H), 7.44-7.36 (m, 2H), 7.36-7.27 (m, 2H), 7.22-7.14 (m, 2H), 6.60-6.43 (m, 1H), 6.11 (dd, J=8.3, 0.8 Hz, 1H), 4.25 (qd, J=5.7, 4.2 Hz, 1H), 4.04-3.81 (m, 2H), 2.77-2.53 (m, 2H), 2.29-1.87 (m, 4H). MS (M+H) found for C₁₉H₁₉NO₄: 326.5.

GBT1717—6-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-2,3-dimethoxybenzaldehyde. The compound was prepared by O-alkylation of 6-hydroxy-2,3-dimethoxybenzaldehyde (A) and 3-(chloromethyl)-2-[1-(propan-2-yl)-1H-pyrazol-5-yl]pyridine hydrochloride salt (INT-2) according to scheme 9, reaction step 4. The product as white solid was obtained after flash column purification. ¹H NMR (400 MHz, Chloroform-d) δ 10.49 (t, J=0.4 Hz, 1H), 8.69 (dd, J=4.8, 1.7 Hz, 1H), 8.29 (ddd, J=8.0, 1.7, 0.9 Hz, 1H), 7.61 (dd, J=1.9, 0.5 Hz, 1H), 7.44 (dd, J=7.9, 4.8 Hz, 1H), 7.03 (d, J=9.0 Hz, 1H), 6.52 (d, J=7.9 Hz, 1H), 6.36 (dd, J=1.9, 0.4 Hz, 1H), 4.98 (s, 2H), 4.59 (hept, J=6.7 Hz, 1H), 3.95 (d, J=0.4 Hz, 3H), 3.84 (s, 3H), 1.46 (d, J=6.6 Hz, 6H). MS (M+H) found for C₂₁H₂₃N₃O₄: 382.5.

Preparation of Intermediate A

Step 1: To a suspension of 3,4-dimethoxyphenol (2.0 g, 12.97 mmol) in dihydropyran (2 mL, 21.87 mmol) at ambient temperature was added 1 drop of Cone. HCl. After stirred for 1 h, the solution was diluted with EtOAc, organic layer was washed with Sat. NaHCO3, brine, dried and concentrated to give crude product, which was purified by column (Hexanes/EtOAc=65:35) to give 2-(3,4-dimethoxyphenoxy)tetrahydro-2H-pyran (2.9 g).

Step 2: To a solution of 2-(3,4-dimethoxyphenoxy)tetrahydro-2H-pyran (1.0 g, 4.2 mmol) in THF (6 mL) at 0° C. was added TMEDA (0.72 mL, 4.83 mmol) and BuLi (2.5 M, 2.02 mL, 5.05 mmol). After stirred for 1.5 h at 0° C., it was added DMF (1.3 mL). After stirred for 1 h, the mixture was added 6N HCl (4 mL), and was stirred for 1 h at ambient temperature, additional 12N HCl (2 mL) was added to drive the reaction to completion. The solution was diluted with EtOAc and water, organic layer was separated and washed with brine, dried and concentrated to give crude product, which was purified by column chromatography to give 6-hydroxy-2,3-dimethoxybenzaldehyde (490 mg).

2,3-dihydroxy-6-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde GBT1659—2,3-dihydroxy-6-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde

To a solution of 6-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-2,3-dimethoxybenzaldehyde (24 mg, 0.03 mmol) was added BBr₃ (1M, 0.3 mL), after stirred at ambient temperature for 30 min, the mixture was concentrated and the crude product was purified by preparative HPLC to give 2,3-dihydroxy-6-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde (10 mg). ¹H NMR (400 MHz, Chloroform-d) δ 12.01 (s, 1H), 10.32 (d, J=0.5 Hz, 1H), 8.74 (dd, J=4.8, 1.7 Hz, 1H), 8.00-7.92 (m, 1H), 7.60 (dd, J=1.9, 0.6 Hz, 1H), 7.41 (dd, J=7.9, 4.8 Hz, 1H), 7.03 (d, J=8.8 Hz, 1H), 6.34 (d, J=1.9 Hz, 1H), 6.19 (d, J=8.8 Hz, 1H), 5.29 (s, 1H), 5.02 (s, 2H), 4.64 (hept, J=6.6 Hz, 1H), 1.47 (d, J=6.6 Hz, 6H). MS (M+H) found for C₁₉H₁₉N₃O₄:354.4.

2-hydroxy-6-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-3-methoxybenzaldehyde GBT1718—2-hydroxy-6-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-3-methoxybenzaldehyde

To a solution of 6-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-2,3-dimethoxybenzaldehyde (30.00 mg; 0.13 mmol) in DCM (0.8 mL) at ambient temperature was added boron tribromide (0.13 ml; 1.00 mol/1). After stirred for 3 min, the red mixture was concentrated and the crude product was purified by preparative HPLC to give 2-hydroxy-6-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-3-methoxybenzaldehyde (15 mg). ¹H NMR (400 MHz, Chloroform-d) δ 12.15 (d, J=0.6 Hz, 1H), 10.35 (s, 1H), 8.74 (dd, J=4.8, 1.7 Hz, 1H), 7.97 (ddd, J=7.9, 1.6, 0.7 Hz, 1H), 7.60 (dd, J=1.8, 0.5 Hz, 1H), 7.41 (dd, J=7.9, 4.8 Hz, 1H), 6.98-6.94 (m, 1H), 6.34 (d, J=1.9 Hz, 1H), 6.18 (d, J=8.9 Hz, 1H), 5.02 (s, 2H), 4.72-4.57 (m, 1H), 3.84 (s, 3H), 1.47 (d, J=6.6 Hz, 6H). MS (M+H) found for C₂₀H₂₁N₃O₄: 368.4.

GBT001723—2-((6-((2-(dimethylamino)ethyl)(methyl)amino)-2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-6-hydroxybenzaldehyde. The compound was prepared by Mitsunobu coupling of (6-((2-(dimethylamino)ethyl)(methyl)amino)-2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methanol (A) with 2,6-dihydroxybenzaldehyde (INT-3) according to scheme 9, reaction step 3. The product as green oil was obtained after flash column purification. ¹HNMR (400 MHz, CDCl₃, ppm): 11.87 (br s, 1H), 10.21 (s, 1H), 7.54 (d, J=8.8 Hz, 1H), 7.44 (s, 1H), 7.26 (t, J=8.4 Hz, 1H), 6.50 (d, J=8.8 Hz, 1H), 6.41 (d, J=8.4 Hz, 1H), 6.20 (d, J=8.4 Hz, 1H), 6.18 (s, 1H), 4.82 (s, 2H), 4.90-4.60 (m, 1H), 3.61 (t, J=11.2 Hz, 2H), 3.03 (s, 3H), 2.43 (t, J=11.2 Hz, 2H), 2.20 (s, 6H), 1.39 (d, J=6.8 Hz, 6H); MS(ES, m/z:) 438.4 [M+1]⁺

Intermediate A was prepared followed the scheme below:

Step 1: Into a 25-mL round-bottom flask, was placed a solution of methyl 6-bromo-2-[1-(propan-2-yl)-1H-pyrazol-5-yl]pyridine-3-carboxylate (1.3 g, 4.01 mmol, 1.00 equiv) in tetrahydrofuran (13 mL). DIPEA (1.33 g, 3.00 equiv) and [2-(dimethylamino)ethyl](methyl)amine (2.4 g, 23.49 mmol, 3.00 equiv) were added to the reaction mixture. The resulting solution was heated to reflux for 24 hr, and then it was quenched with 30 mL of water. The resulting solution was extracted with 3×30 mL of ethyl acetate. The combined organic layers were washed with 1×80 mL of water and 1×80 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (30:1-13:1) as eluent to furnish 1.22 g (88%) of methyl 6-[[2-(dimethylamino)ethyl](methyl)amino]-2-[1-(propan-2-yl)-1H-pyrazol-5-yl]pyridine-3-carboxylate as a light yellow oil.

Step 2. Into a 100-mL round-bottom flask, was placed a solution of methyl 6-[[2-(dimethylamino)ethyl](methyl)amino]-2-[1-(propan-2-yl)-1H-pyrazol-5-yl]pyridine-3-carboxylate (1.2 g, 3.47 mmol, 1.00 equiv) in tetrahydrofuran (20 mL). This was followed by the addition of LAH (330 mg, 8.70 mmol, 2.30 equiv), in portions at 0° C. The resulting solution was stirred for 4 h at room temperature. The reaction was quenched by the addition of 0.3 mL water, 0.3 mL 2.3M sodium hydroxide (aq.). The resulting solution was diluted with 30 mL of ethyl acetate. The solids were filtered out and washed with THF for 3 times. The resulting mixture was concentrated under vacuum. This resulted in 1.1 g (100%) of (6-[[2-(dimethylamino)ethyl](methyl)amino]-2-[1-(propan-2-yl)-1H-pyrazol-5-yl]pyridin-3-yl)methanol as a colorless oil.

From the foregoing it will be appreciated that, although specific embodiments of the invention have been described herein for purposes of illustration, various modifications may be made without deviating from the spirit and scope of the invention.

Throughout the description of this invention, reference is made to various patent applications and publications, each of which are herein incorporated by reference in their entirety.

As used herein, Table 1 includes compounds described below or tautomers or pharmaceutically acceptable salts thereof:

-   2-(imidazo[1,2-a]pyridin-8-ylmethoxy)-5-methoxybenzaldehyde, -   2-(imidazo[1,2-a]pyridin-2-ylmethoxy)-5-methoxybenzaldehyde, -   2-(imidazo[1,5-a]pyridin-8-ylmethoxy)-5-methoxybenzaldehyde, -   5-methoxy-2-(quinolin-5-ylmethoxy)benzaldehyde, -   5-methoxy-2-((1-methyl-1H-indazol-4-yl)methoxy)benzaldehyde, -   5-methoxy-2-((8-methylimidazo[1,2-a]pyridin-2-yl)methoxy)benzaldehyde, -   2-((1H-indazol-4-yl)methoxy)-5-methoxybenzaldehyde, -   5-methoxy-2-(pyridin-3-ylmethoxy)benzaldehyde, -   2-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-5-methoxy)benzaldehyde, -   2-hydroxy-6-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde, -   2-((3-(2H-tetrazol-5-yl)benzyl)oxy)-6-hydroxybenzaldehyde, -   2-((4-(2H-tetrazol-5-yl)benzyl)oxy)-6-hydroxybenzaldehyde, -   methyl 4-((2-formylphenoxy)methyl)benzoate, -   4-((2-formylphenoxy)methyl)benzoic acid, -   methyl 3-((2-formylphenoxy)methyl)benzoate, -   2-bromo-3-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde, -   2-hydroxy-6-((2-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde, -   2-hydroxy-6-((2-(1-(3,3,3-trifluoropropyl)-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde, -   2-fluoro-6-((2-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde, -   2-fluoro-6-((2-(1-(3,3,3-trifluoropropyl)-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde, -   2-fluoro-6-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde,     and -   1-(2-formyl-3-hydroxyphenethyl)piperidine-4-carboxylic acid, or a     tautomer or pharmaceutically acceptable salt thereof.

Compound Structure Name 1

2-(imidazo[1,2-a]pyridin-8- ylmethoxy)-5-methoxybenzaldehyde 2

4-formyl-3-(imidazo[1,2-a]pyridin-8- ylmethoxy)benzonitrile 3

2-(imidazo[1,2-a]pyridin-8- ylmethoxy)-4-methoxybenzaldehyde 4

2-(imidazo[1,2-a]pyridin-6- ylmethoxy)-5-methoxybenzaldehyde 5

2-(imidazo[1,2-a]pyridin-2- ylmethoxy)-5-methoxybenzaldehyde 6

2-(imidazo[1,5-a]pyridin-8- ylmethoxy)-4-methoxybenzaldehyde 7

2-(imidazo[1,5-a]pyridin-8- ylmethoxy)-5-methoxybenzaldehyde 8

2-(imidazo[1,2-a]pyridin-7- ylmethoxy)-5-methoxybenzaldehyde 9

2-(imidazo[1,2-a]pyridin-8- ylmethoxy)-5-methoxybenzaldehyde 10

5-methoxy-2-(quinolin-5- ylmethoxy)benzaldehyde 11

5-bromo-2-(imidazo[1,2-a]pyridin-8- ylmethoxy)benzaldehyde 12

4-chloro-2-(imidazo[1,2-a]pyridin-8- ylmethoxy)benzaldehyde 13

2-(imidazo[1,2-a]pyridin-8- ylmethoxy)benzaldehyde 14

4-fluoro-2-(imidazo[1,2-a]pyridin-8- ylmethoxy)benzaldehyde 15

2-(imidazo[1,2-a]pyridin-8- ylmethoxy)-3-methoxybenzaldehyde 16

2-(imidazo[1,2-a]pyridin-8- ylmethoxy)-5-methylbenzaldehyde 17

5-methoxy-2-(pyrrolo[1,2-a]pyrazin-4- ylmethoxy)benzaldehyde 18

2-(imidazo[1,5-a]pyridin-6- ylmethoxy)-4-methoxybenzaldehyde 19

2-(imidazo[1,5-a]pyridin-5- ylmethoxy)-5-methoxybenzaldehyde 20

3-formyl-4-(imidazo[1,5-a]pyridin-5- ylmethoxy)benzonitrile 21

2-((1H-pyrrolo[2,3-b]pyridin-4- yl)methoxy)-5-methoxybenzaldehyde 22

5-ethyl-2-(imidazo[1,2-a]pyridin-8- ylmethoxy)benzaldehyde 23

5-methoxy-2-((1-methyl-1H-indazol-4- yl)methoxy)benzaldehyde 24

5-methoxy-2-((8-methylimidazo[1,2- a]pyridin-2-yl)methoxy)benzaldehyde 25

2-((1H-indazol-4-yl)methoxy)-5- methoxybenzaldehyde 26

2-((1H-pyrrolo[2,3-b]pyridin-4- yl)methoxy)-5-methoxybenzaldehyde 27

3-formyl-4-(imidazo[1,2-a]pyridin-8- ylmethoxy)benzonitrile 28

5-methoxy-2-(pyrrolo[1,2-a]pyrazin-6- ylmethoxy)benzaldehyde 29

6-((2-formyl-4- methoxyphenoxy)methyl)pyrrolo[1,2- a]pyrazine-7-carbonitrile 30

6-((2-formyl-4- methoxyphenoxy)methyl)pyrrolo[1,2- a]pyrazine-7-carboxamide 31

2-((1H-pyrazolo[3,4-b]pyridin-4- yl)methoxy)-5-methoxybenzaldehyde 32

5-methoxy-2-(pyrazolo[1,5-a]pyrazin- 3-ylmethoxy)benzaldehyde 33

5-methoxy-2-(pyrrolo[1,2-a]pyrazin-6- ylmethoxy)benzaldehyde 34

2-(imidazo[1,5-a]pyridin-6- ylmethoxy)-5-methoxybenzaldehyde 35

3-formyl-4-(imidazo[1,2-a]pyridin-8- ylmethoxy)benzonitrile 36

3-(imidazo[1,2-a]pyridin-8-ylmethyl)- 1,3-dihydroisobenzofuran-1-ol 37

2-(imidazo[1,2-a]pyridin-5- ylmethoxy)-5-methoxybenzaldehyde 38

N-(2-formyl-4- methoxyphenyl)imidazo[1,2- a]pyridine-8-carboxamide 39

N-(2-formylphenyl)imidazo[1,2- a]pyridine-8-carboxamide 40

2-formyl-N-(imidazo[1,2-a]pyridin-8- yl)benzamide 41

5-methoxy-2-(pyridin-3- ylmethoxy)benzaldehyde 42

4-((2-formyl-3- hydroxyphenoxy)methyl)benzoic acid 43

2-hydroxy-6-((2-(1-isopropyl-1H- pyrazol-5-yl)pyridin-3- yl)methoxy)benzaldehyde 44

2-((3-(2H-tetrazol-5-yl)benzyl)oxy)-6- hydroxybenzaldehyde 45

2-((4-(2H-tetrazol-5-yl)benzyl)oxy)-6- hydroxybenzaldehyde 46

methyl 4-((2- formylphenoxy)methyl)benzoate 47

4-((2-formylphenoxy)methyl)benzoic acid 48

methyl 3-((2- formylphenoxy)methyl)benzoate 49

2-bromo-3-((2-(1-isopropyl-1H- pyrazol-5-yl)pyridin-3- yl)methoxy)benzaldehyde 50

2-hydroxy-6-((2-(1-(2,2,2- trifluoroethyl)-1H-pyrazol-5-yl)pyridin- 3-yl)methoxy)benzaldehyde 51

2-hydroxy-6-((2-(1-(3,3,3- trifluoropropyl)-1H-pyrazol-5- yl)pyridin-3-yl)methoxy)benzaldehyde 52

2-fluoro-6-((2-(1-(2,2,2-trifluoroethyl)- 1H-pyrazol-5-yl)pyridin-3- yl)methoxy)benzaldehyde 53

2-fluoro-6-((2-(1-(3,3,3- trifluoropropyl)-1H-pyrazol-5- yl)pyridin-3-yl)methoxy)benzaldehyde 54

2-fluoro-6-((2-(1-isopropyl-1H- pyrazol-5-yl)pyridin-3- yl)methoxy)benzaldehyde 55

1-(2-formyl-3- hydroxyphenethyl)piperidine-4- carboxylic acid 1

4-(pyridin-3- ylmethoxy)nicotinaldehyde 2

3-(pyridin-3- ylmethoxy)isonicotinaldehyde 3

2-(imidazo[1,2-a]pyridin-8- ylmethoxy)nicotinaldehyde 4

3-(imidazo[1,2-a]pyridin-8- ylmethoxy)picolinaldehyde 5

5-(imidazo[1,2-a]pyridin-8- ylmethoxy)-2- methoxyisonicotinaldehyde 6

3-(imidazo[1,2-a]pyridin-8- ylmethoxy)isonicotinaldehyde 7

3-(imidazo[1,5-a]pyridin-8- ylmethoxy)isonicotinaldehyde 8

2-methoxy-5-(pyrazolo[1,5- a]pyrazin-3- ylmethoxy)isonicotinaldehyde 9

8-((3-formylpyridin-2- yloxy)methyl)imidazo[1,2- a]pyridine-6-carboxamide 10

8-((4-formyl-6-methoxypyridin-3- yloxy)methyl)imidazo[1,2- a]pyridine-6-carboxamide 11

5-(imidazo[1,2-a]pyridin-8- ylmethoxy)-2-oxo-1,2- dihydropyridine-4-carbaldehyde 12

2-(2-(imidazo[1,2-a]pyridin-8- yl)ethyl)nicotinaldehyde 13

5-(2-(imidazo[1,2-a]pyridin-8- yl)ethyl)-2- methoxyisonicotinaldehyde 14

5-((1H-pyrazolo[3,4-b]pyridin-4- yl)methoxy)-2- methoxyisonicotinaldehyde 15

3-((4-formyl-6-methoxypyridin-3- yloxy)methyl)pyrazolo[1,5- a]pyrazine-2-carboxamide 16

5-((2-(1H-pyrazol-5- yl)pyrazolo[1,5-a]pyrazin-3- yl)methoxy)-2- methoxyisonicotinaldehyde 17

2-(imidazo[1,2-a]pyridin-2- ylmethoxy)nicotinaldehyde 18

2-methoxy-5-((4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazin- 3-yl)methoxy)isonicotinaldehyde 19

2-(imidazo[1,2-a]pyridin-8- ylmethoxy)nicotinaldehyde 20

5-(imidazo[1,2-a]pyridin-8- ylmethoxy)-2- methylisonicotinaldehyde 21

3-((1H-pyrrolo[2,3-b]pyridin-4- yl)methoxy)isonicotinaldehyde 22

3-(imidazo[1,2-a]pyridin-8- ylmethoxy)isonicotinaldehyde 23

3-(pyrrolo[1,2-a]pyrazin-6- ylmethoxy)isonicotinaldehyde 24

6-((4-formylpyridin-3- yloxy)methyl)pyrrolo[1,2- a]pyrazine-7-carbonitrile 25

6-((4-formylpyridin-3- yloxy)methyl)pyrrolo[1,2- a]pyrazine-7-carboxamide 26

3-((1H-pyrazolo[3,4-b]pyridin-4- yl)methoxy)isonicotinaldehyde 27

3-(pyrazolo[1,5-a]pyrazin-3- ylmethoxy)isonicotinaldehyde 28

2-methoxy-5-((6-oxo-1,6- dihydropyridin-3- yl)methoxy)isonicotinaldehyde 29

2-methoxy-5-((2-oxo-1,2- dihydropyridin-4- yl)methoxy)isonicotinaldehyde 30

2-methoxy-5-(oxazol-5- ylmethoxy)isonicotinaldehyde 31

5-((1H-imidazol-5-yl)methoxy)-2- methoxyisonicotinaldehyde 32

5-((1H-imidazol-2-yl)methoxy)-2- methoxyisonicotinaldehyde 33

5-((4H-1,2,4-triazol-3- yl)methoxy)-2- methoxyisonicotinaldehyde 34

5-((1H-tetrazol-5-yl)methoxy)-2- methoxyisonicotinaldehyde 35

5-((1H-pyrazol-5-yl)methoxy)-2- methoxyisonicotinaldehyde 36

5-((1H-pyrazol-4-yl)methoxy)-2- methoxyisonicotinaldehyde 37

2-methoxy-5-(oxazol-4- ylmethoxy)isonicotinaldehyde 38

2-methoxy-5-((2-methylpyridin-3- yl)methoxy)isonicotinaldehyde 39

2-methoxy-5-((4-methylpyridin-3- yl)methoxy)isonicotinaldehyde 40

2-methoxy-5-((6- (trifluoromethyl)pyridin-3- yl)methoxy)isonicotinaldehyde 41

2-methoxy-5-((6-methylpyridin-3- yl)methoxy)isonicotinaldehyde 42

2-methoxy-5-(pyridin-3- ylmethoxy)isonicotinaldehyde 43

2-methoxy-5-((5-methylpyridin-3- yl)methoxy)isonicotinaldehyde 44

5-(isoquinolin-1-ylmethoxy)-2- methoxyisonicotinaldehyde 45

2-methoxy-5-(quinolin-2- ylmethoxy)isonicotinaldehyde 46

2-methoxy-5-(pyridin-4- ylmethoxy)isonicotinaldehyde 47

2-methoxy-5-((3-methylpyridin-4- yl)methoxy)isonicotinaldehyde 48

5-((3-bromopyridin-4- yl)methoxy)-2- methoxyisonicotinaldehyde 49

3-(imidazo[1,2-a]pyridin-8- ylmethoxy)-6- methylpicolinaldehyde 50

(5-(imidazo[1,2-a]pyridin-5- ylmethoxy)-2-methoxypyridin-4- yl)(methoxy)methanol 51

N-(4-formylpyridin-3- yl)imidazo[1,2-a]pyridine-8- carboxamide 52

2-methoxy-5-((6- (trifluoromethyl)imidazo[1,2- a]pyridin-2- yl)methoxy)isonicotinaldehyde 53

methyl 2-((4-formyl-6- methoxypyridin-3- yloxy)methyl)imidazo[1,2- a]pyridine-8-carboxylate 54

2-methoxy-5-((1-methyl-2-oxo- 1,2-dihydropyridin-4- yl)methoxy)isonicotinaldehyde 55

5-((3-bromoimidazo[1,2-a]pyridin- 2-yl)methoxy)-2- methoxyisonicotinaldehyde 56

5-((6-bromoimidazo[1,2-a]pyridin- 2-yl)methoxy)-2- methoxyisonicotinaldehyde 57

5-((8-bromoimidazo[1,2-a]pyridin- 2-yl)methoxy)-2- methoxyisonicotinaldehyde 58

2-methoxy-5-((3-methyl- [1,2,4]triazolo[4,3-a]pyridin-8- yl)methoxy)isonicotinaldehyde 59

5-((3-(1H-pyrazol-5- yl)imidazo[1,2-a]pyridin-2- yl)methoxy)-2- methoxyisonicotinaldehyde 60

5-((6-(1H-pyrazol-3- yl)imidazo[1,2-a]pyridin-2- yl)methoxy)-2- methoxyisonicotinaldehyde 61

2-methoxy-5-((8-(1-methyl-1H- pyrazol-5-yl)imidazo[1,2- a]pyridin-2- yl)methoxy)isonicotinaldehyde 62

5-((4-formyl-6-methoxypyridin-3- yloxy)methyl)picolinonitrile 63

5-((2-bromopyridin-3- yl)methoxy)-2- methoxyisonicotinaldehyde 64

3-((4-formyl-6-methoxypyridin-3- yloxy)methyl)picolinonitrile 65

5-((2-(1H-pyrazol-5-yl)pyridin-3- yl)methoxy)-2- methoxyisonicotinaldehyde 66

5-((5-bromopyridin-3- yl)methoxy)-2- methoxyisonicotinaldehyde 67

methyl 2-((4-(1,3-dioxolan-2-yl)- 6-methoxypyridin-3- yloxy)methyl)imidazo[1,2- a]pyridine-8-carboxylate 68

2-((4-(1,3-dioxolan-2-yl)-6- methoxypyridin-3- yloxy)methyl)imidazo[1,2- a]pyridine-8-carboxamide 69

2-((4-(1,3-dioxolan-2-yl)-6- methoxypyridin-3-yloxy)methyl)- N-methylimidazo[1,2-a]pyridine- 8-carboxamide 70

5-((5-(1H-pyrazol-5-yl)pyridin-3- yl)methoxy)-2- methoxyisonicotinaldehyde 71

5-((4-(1H-pyrazol-5-yl)pyridin-3- yl)methoxy)-2- methoxyisonicotinaldehyde 72

2-((4-(dihydroxymethyl)-6- methoxypyridin-3-yloxy)methyl)- N-methylimidazo[1,2-a]pyridine- 8-carboxamide 73

2-((4-(dihydroxymethyl)-6- methoxypyridin-3- yloxy)methyl)imidazo[1,2- a]pyridine-8-carboxamide 74

2-methoxy-5-((5-(1-methyl-1H- pyrazol-5-yl)pyridin-3- yl)methoxy)isonicotinaldehyde 75

2-methoxy-5-((5-(1-methyl-1H- pyrazol-3-yl)pyridin-3- yl)methoxy)isonicotinaldehyde 76

5-((5-(1H-pyrazol-4-yl)pyridin-3- yl)methoxy)-2- methoxyisonicotinaldehyde 77

2-methoxy-5-((5-(1-methyl-1H- pyrazol-4-yl)pyridin-3- yl)methoxy)isonicotinaldehyde 78

methyl 5-((4-formyl-6- methoxypyridin-3- yloxy)methyl)nicotinate 79

5-((4-formyl-6-methoxypyridin-3- yloxy)methyl)nicotinic acid 80

2-methoxy-5-(quinolin-3- ylmethoxy)isonicotinaldehyde 81

6-methyl-3-(quinolin-3- ylmethoxy)picolinaldehyde 82

5-(isoquinolin-7-methoxy)-2- methoxyisonicotinaldehyde 83

3-(isoquinolin-7-methoxy)-6- methylpicolinaldehyde 84

2-methoxy-5-((1-methyl-1H- indazol-4- yl)methoxy)isonicotinaldehyde 85

6-methyl-3-((1-methyl-1H- indazol-4- yl)methoxy)picolinaldehyde 86

tert-butyl 4-((2-formyl-6- methylpyridin-3-yloxy)methyl)- 1Hindazole-1-carboxylate 87

5-((1H-indazol-4-yl)methoxy)-2- methoxyisonicotinaldehyde 88

3-((1H-indazol-4-yl)methoxy)-6- methylpicolinaldehyde 89

6-methoxy-3-((1-methyl-1H- indazol-6- yl)methoxy)picolinaldehyde 90

2-methoxy-5-((1-methyl-1H- indazol-7- yl)methoxy)isonicotinaldehyde 91

6-methyl-3-((1-methyl-1H- indazol-6- yl)methoxy)picolinaldehyde 92

6-methyl-3-((1-methyl-1H- indazol-7- yl)methoxy)picolinaldehyde 93

3-(isoquinolin-1-ylmethoxy)-6- methylpicolinaldehyde 94

6-methyl-3-(quinolin-2- ylmethoxy)picolinaldehyde 95

5-((4-(1H-pyrazol-4-yl)pyridin-3- yl)methoxy)-2- methoxyisonicotinaldehyde 96

5-((6-bromoimidazo[1,2-a]pyridin- 8-yl)methoxy)-2- methoxyisonicotinaldehyde 97

8-((4-formyl-6-methoxypyridin-3- yloxy)methyl)imidazo[1,2- a]pyridine-6-carbonitrile 98

5-((4-formyl-6-methoxypyridin-3- yloxy)methyl)nicotinonitrile 99

3-(benzo[d]oxazol-4-ylmethoxy)- 6-methylpicolinaldehyde 100

8-((4-formyl-6-methoxypyridin-3- yloxy)methyl)imidazo[1,2- a]pyridine-6-carboxamide 101

5-((4-formyl-6-methoxypyridin-3- yloxy)methyl)nicotinamide 102

5-((6-(1H-pyrazol-4- yl)imidazo[1,2-a]pyridin-8- yl)methoxy)-2- methoxyisonicotinaldehyde 103

5-(benzo[d]oxazol-4-ylmethoxy)- 2-methoxyisonicotinaldehyde 104

5-((6-(1H-pyrazol-5- yl)imidazo[1,2-a]pyridin-8- yl)methoxy)-2- methoxyisonicotinaldehyde 105

5-((1,5-naphthyridin-4- yl)methoxy)-2- methoxyisonicotinaldehyde 106

3-((1,5-naphthyridin-4- yl)methoxy)-6- methylpicolinaldehyde 107

5-((1H-indaozl-5-yl)methoxy)-2- methoxyisonicotinaldehyde 108

6-methyl-3-((1-methyl-1H- indazol-5- yl)methoxy)picolinaldehyde 109

3-((3-chloro-1-methyl-1H-indazol- 5-yl)methoxy)-6- methylpicolinaldehyde 110

2-methoxy-5-((1-methyl-1H- indazol-5- yl)methoxy)isonicotinaldehyde 111

5-((3-chloro-1-methyl-1H-indazol- 5-yl)methoxy)-2- methoxyisonicotinaldehyde 112

N-(4-formyl-6-methoxypyridin-3- yl)imidazo[1,2-a]pyridine-8- carboxamide 113

3-((1,3-dimethyl-1H-pyrazolo[3,4- b]pyridin-4-yl)methoxy)-6- methylpicolinaldehyde 114

5-((1,3-dimethyl-1H-pyrazolo[3,4- b]pyridin-4-yl)methoxy)-2- methoxyisonicotinaldehyde 115

3-((4-formyl-6-methoxypyridin-3- yloxy)methyl)picolinamide 116

5-((2-chloroquinolin-3- yl)methoxy)-2- methoxyisonicotinaldehyde 117

5-((2-(1H-pyrazol-5-yl)quinolin-3- yl)methoxy)-2- methoxyisonicotinaldehyde 118

2-methoxy-5-(quinoxalin-2- ylmethoxy)isonicotinaldehyde 119

6-methyl-3-(quinolin-5- ylmethoxy)picolinaldehyde 120

2-methoxy-5-(quinolin-5- ylmethoxy)isonicotinaldehyde 121

6-methyl-3-((1-methyl-1H- pyrazolo[3,4-b]pyridin-5- yl)methoxy)picolinaldehyde 122

2-methoxy-5-((1-methyl-1H- pyrazolo[3,4-b]pyridin-5- yl)methoxy)isonicotinaldehyde 123

5-((7-(1H-pyrazol-3- yl)imidazo[1,5-a]pyridin-8- yl)methoxy)-2- methoxyisonicotinaldehyde 124

5-((5-(2H-tetrazol-5-yl)pyridin-3- yl)methoxy)-2- methoxyisonicotinaldehyde 125

5-((6-(2H-tetrazol-5- yl)imidazo[1,2-a]pyridin-8- yl)methoxy)-2- methoxyisonicotinaldehyde 126

ethyl 2-(5-(imidazo[1,2-a]pyridin- 8-ylmethoxy)-2-methoxypyridin- 4-yl)thiazolidine-4-carboxylate 127

2-methoxy-5-((2-(1-methyl-1H- pyrazol-4-yl)pyridin-3- yl)methoxy)isonicotinaldehyde 128

5-((2-(1H-pyrazol-4-yl)pyridin-3- yl)methoxy)-2- methoxyisonicotinaldehyde 129

2-methoxy-5-((2-(1-methyl-1H- pyrazol-5-yl)pyridin-3- yl)methoxy)isonicotinaldehyde 130

2-methoxy-5-((2-(1-methyl-1H- pyrazol-3-yl)pyridin-3- yl)methoxy)isonicotinaldehyde 131

5-((2-(2H-tetrazol-5-yl)pyridin-3- yl)methoxy)-2- methoxyisonicotinaldehyde 132

2-methoxy-5-((2-(4-methyl-1H- pyrazol-5-yl)pyridin-3- yl)methoxy)isonicotinaldehyde 133

5-((3-(1H-pyrazol-5- yl)isoquinolin-4-yl)methoxy)-2- methoxyisonicotinaldehyde 134

5-((2-(1H-pyrazol-1-yl)pyridin-3- yl)methoxy)-2- methoxyisonicotinaldehyde 135

3-((2-(1H-pyrazol-1-yl)pyridin-3- yl)methoxy)-6- methylpicolinaldehyde 136

6-methyl-3-(pyridin-3- ylmethoxy)picolinaldehyde 137

methyl 8-(((4-formyl-6- methoxypyridin-3- yl)oxy)methyl)imidazo[1,2- a]pyridine-6-carboxylate 138

methyl 2-bromo-8-(((4-formyl-6- methoxypyridin-3- yl)oxy)methyl)imidazo[1,2- a]pyridine-6-carboxylate 139

3-(imidazo[1,5-a]pyridin-8- ylmethoxy)-6- methylpicolinaldehyde 140

5-(imidazo[1,5-a]pyridin-8- ylmethoxy)-2- methoxyisonicotinaldehyde 141

(5-(methoxycarbonyl)pyridin-3- yl)methyl 5-(((4-formyl-6- methoxypyridin-3- yl)oxy)methyl)nicotinate 142

5-((2-(1,4-dimethyl-1H-pyrazol-5- yl)pyridin-3-yl)methoxy)-2- methoxyisonicotinaldehyde 143

5-((2-(1,5-dimethyl-1H-pyrazol-4- yl)pyridin-3-yl)methoxy)-2- methoxyisonicotinaldehyde 144

2-hydroxyethyl 5-(((4-(1,3- dioxolan-2-yl)-6-methoxypyridin- 3-yl)oxy)methyl)nicotinate 145

methyl 5-(((4-(1,3-dioxolan-2-yl)- 6-methoxypyridin-3- yl)oxy)methyl)nicotinate 146

methyl 5-(((4-(bis(2- hydroxyethoxy)methyl)-6- methoxypyridin-3- yl)oxy)methyl)nicotinate 147

5-((2-(1,3-dimethyl-1H-pyrazol-4- y)pyridin-3-yl)methoxy)-2- methoxyisonicotinaldehyde 148

5-((2-(1,3-dimethyl-1H-pyrazol-5- yl)pyridin-3-yl)methoxy)-2- methoxyisonicotinaldehyde 149

5-((2-(1-ethyl-1H-pyrazol-5- yl)pyridin-3-yl)methoxy)-2- methoxyisonicotinaldehyde 150

5-((2-(1-isopropyl-1H-pyrazol-5- yl)pyridin-3-yl)methoxy)-2- methoxyisonicotinaldehyde 151

2-methoxy-5-((2-(3-methyl-1H- pyrazol-1-yl)pyridin-3- yl)methoxy)isonicotinaldehyde 152

5-(((4-(1,3-dioxolan-2-yl)-6- methoxypyridin-3- yl)oxy)methyl)nicotinic acid 153

(E)-2-methoxy-5-((2-(4-methyl- 1H-pyrazol-5-yl)pyridin-3- yl)methoxy)isonicotinaldehyde oxime 154

(E)-2-methoxy-5-(pyridin-3- ylmethoxy)isonicotinaldehyde oxime 155

2-(5-(imidazo[1,2-a]pyridin-8- ylmethoxy)-2-methoxypyridin-4- yl)thiazolidine 156

1-(2-(5-(imidazo[1,2-a]pyridin-8- ylmethoxy)-2-methoxypyridin-4- yl)thiazolidin-3-yl)ethanone 157

5-((2-(4-(1H-pyrazol-3- yl)piperazin-1-yl)pyridin-3- yl)methoxy)-2- methoxyisonicotinaldehyde 158

2-(difluoromethoxy)-5- (imidazo[1,2-a]pyridin-8- ylmethoxy)isonicotinaldehyde 159

2-methoxy-5-((2-phenylpyridin-3- yl)methoxy)isonicotinaldehyde 160

5-((3-(1-isopropyl-1H-pyrazol-5- yl)pyridin-4-yl)methoxy)-2- methoxyisonicotinaldehyde 161

5-([2,3′-bipyridin]-3-ylmethoxy)- 2-methoxyisonicotinaldehyde 162

2-methoxy-5-((2-(o-tolyl)pyridin- 3-yl)methoxy)isonicotinaldehyde 163

2-methoxy-5-((2′-methoxy-[2,3′- bipyridin]-3- yl)methoxy)isonicotinaldehyde 164

methyl 4-(((2-formylpyridin-3- yl)oxy)methyl)benzoate 165

4-(((2-formyl-6-methylpyridin-3- yl)oxy)methyl)benzoic acid 166

4-(((2-formylpyridin-3- yl)oxy)methyl)benzoic acid 167

methyl 3-(((4-formylpyridin-3- yl)oxy)methyl)benzoate 168

methyl 3-(((2-formyl-6- methylpyridin-3- yl)oxy)methyl)benzoate 169

3-(((4-formylpyridin-3- yl)oxy)methyl)benzoic acid 170

3-(((2-formyl-6-methylpyridin-3- yl)oxy)methyl)benzoic acid 171

3-(((2-formylpyridin-3- yl)oxy)methyl)benzoic acid 172

2-methoxy-5-((2-(1-(2- methoxyethyl)-1H-pyrazol-5- yl)pyridin-3- yl)methoxy)isonicotinaldehyde 173

2-methoxy-5-((2-(1-propyl-1H- pyrazol-5-yl)pyridin-3- yl)methoxy)isonicotinaldehyde 174

2-methoxy-5-((2-(1-(2,2,2- trifluoroethyl)-1H-pyrazol-5- yl)pyridin-3- yl)methoxy)isonicotinaldehyde 175

5-((2-(1-(2,2-difluoroethyl)-1H- pyrazol-5-yl)pyridin-3- yl)methoxy)-2- methoxyisonicotinaldehyde 176

3-((2-(1-isopropyl-1H-pyrazol-5- yl)pyridin-3- yl)methoxy)picolinaldehyde 177

3-((2-(1-isopropyl-1H-pyrazol-5- yl)pyridin-3-yl)methoxy)-6- methylpicolinaldehyde 178

2-(difluoromethoxy)-5-((2-(1- isopropyl-1H-pyrazol-5- yl)pyridin-3- yl)methoxy)isonicotinaldehyde 179

5-(imidazo[1,2-a]pyridin-8- ylmethoxy)-2-(2- methoxyethoxy)isonicotinaldehyde 180

5-((2-(1-isopropyl-1H-pyrazol-5- yl)pyridin-3-yl)methoxy)-2-(2- methoxyethoxy)isonicotinaldehyde 181

5-((3-(1-isopropyl-1H-pyrazol-5- yl)pyrazin-2-yl)methoxy)-2- methoxyisonicotinaldehyde 182

3-((4-formyl-6-methoxypyridin-3- yloxy)methyl)picolinate 183

5-((2-(2-hydroxypropan-2- yl)pyridin-3-yl)methoxy)-2- methoxyisonicotinaldehyde 184

2-(2-methoxyethoxy)-5-((2-(1- methyl-1H-pyrazol-5-yl)pyridin-3- yl)methoxy)isonicotinaldehyde 185

2-(2-methoxyethoxy)-5-((2-(1- methyl-1H-pyrazol-5-yl)pyridin-3- yl)methoxy)nicotinaldehyde 186

3-hydroxy-5-((2-(1-isopropyl-1H- pyrazol-5-yl)pyridin-3- yl)methoxy)isonicotinaldehyde 187

3-(benzyloxy)-5- hydroxyisonicotinaldehyde 188

3-((2-(1-isopropyl-1H-pyrazol-5- yl)pyridin-3-yl)methoxy)-5- methoxyisonicotinaldehyde 189

5-((2-(2-isopropyl-2H-1,2,4- triazol-3-yl)pyridin-3- yl)methoxy)-2- methoxyisonicotinaldehyde 190

5-((2-(1-isopropyl-4-methyl-1H- pyrazol-5-yl)pyridin-3- yl)methoxy)-2- methoxyisonicotinaldehyde 191

5-((2-(1-(2-hydroxyethyl)-1H- pyrazol-5-yl)pyridin-3- yl)methoxy)-2- methoxyisonicotinaldehyde 192

2,2,2-triflurooacetic acid:6-(((4- formylpyridin-3- yl)oxy)methyl)picolinic acid (1:1) 193

2-methoxy-5-((2-(1-((2- (trimethylsilyl)ethoxy)methyl)-1H- pyrazol-5-yl)pyridin-3- yl)methoxy)isonicotinaldehyde 194

5-((2-(4-methyl-1H-pyrazol-5- yl)pyiridin-3-yl)methoxy)-2-oxo- 1,2-dihydropyridine-4- carbaldehyde 195

5-((2-(1-cyclobutyl-1H-pyrazol-5- yl)pyridin-3-yl)methoxy)-2- methoxyisonicotinaldehyde 196

5-((2-(1-cyclohexyl-1H-pyrazol-5- yl)pyridin-3-yl)methoxy)-2- methoxyisonicotinaldehyde 197

5-((2-(1-(cyclohexylmethyl)-1H- pyrazol-5-yl)pyridin-3- yl)methoxy)-2- methoxyisonicotinaldehyde 198

5-((2-(1-cylcopentyl-1H-pyrazol- 5-yl)pyridin-3-yl)methoxy)-2- methoxyisonicotinaldehyde 199

2-(5-(3-((4-formyl-6- methoxypyridin-3- yloxy)methyl)pyridin-2-yl)-1H- pyrazol-1-yl)acetic acid 200

methyl 3-(5-(3-(((4-formyl-6- methoxypyridin-3- yl)oxy)methyl)pyridin-2-yl)-1H- pyrazol-1-yl)propanoate 201

3-(3-(3-((4-formyl-6- methoxypyridin-3- yloxy)methyl)pyridin-2-yl)-1H- pyrazol-1-yl)propanoic acid 202

3-(5-(3-(((4-formyl-6- methoxypyridin-3- yl)oxy)methyl)pyridin-2-yl)-1H- pyrazol-1-yl)propanoic acid 203

3-(((4-formyl-6-methoxypyridin-3- yl)oxy)methyl)benzoic acid 204

6-(((4-formyylpyridin-3- yl)oxy)methyl)nicotinonitrile 2,2,2-trifluoracetate 205

6-(((4-formylpyridin-3- yl)oxy)methyl)nicotinic acid hydrochloride 206

2,2,2-trifluoroacetic acid:6-(((4- formylpyridin-3-yl)oxy)methyl)- N-(methylsulfonyl)nicotinamide (2:1) 207

2-(2-methoxyethoxy)-5-((2-(1- (2,2,2-trifluoroethyl)-1H-pyrazol- 5-yl)pyridin-3- yl)methoxy)isonicotinaldehyde 208

2-methoxy-5-((2-(1-(3,3,3- trifluoropropyl)-1H-pyrazol-5- yl)pyridin-3- yl)methoxy)isonicotinaldehyde 209

2-(2-methoxyethoxy)-5-((2-(1- (3,3,3-trifluoropropyl)-1H- pyrazol-5-yl)pyridin-3- yl)methoxy)isonicotinaldehyde 210

2-methyl-5-((2-(1-(2,2,2- trifluoroethyl)-1H-pyrazol-5- yl)pyridin-3- yl)methoxy)isonicotinaldehyde 211

2-methyl-5-((2-(1-(3,3,3- trifluoropropyl)-1H-pyrazol-5- yl)pyridin-3- yl)methoxy)isonicotinaldehyde 212

3-((2-(1-(2,2,2-trifluoroethyl)-1H- pyrazol-5-yl)pyridin-3- yl)methoxy)isonicotinaldehyde 213

3-((2-(1-(3,3,3-trifluoropropyl)- 1H-pyrazol-5-yl)pyridin-3- yl)methoxy)isonicotinaldehyde 214

3-chloro-5-((2-(1-isopropyl-1H- pyrazol-5-yl)pyridin-3- yl)methoxy)isonicotinaldehyde 215

3-((2-(1-isopropyl-1H-pyrazol-5- yl)pyridin-3-yl)methoxy)-5- methylisonicotinaldehyde 216

3-chloro-5-((2-(1-(3,3,3- trifluoropropyl)-1H-pyrazol-5- yl)pyridin-3- yl)methoxy)isonicotinaldehyde 217

3-methyl-5-((2-(1-(2,2,2- trifluoroethyl)-1H-pyrazol-5- yl)pyridin-3- yl)methoxy)isonicotinaldehyde

The compound is selected from 5-hydroxy-2-(2-methoxyethoxy)isonicotinaldehyde (Compound 218), 5-hydroxy-2-(2-methoxyethoxy)nicotinaldehyde (Compound 219), 5-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-2-oxo-1,2-dihydropyridine-4-carbaldehyde (Compound 220), 5-((2-(4-methyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-2-oxo-1,2-dihydropyridine-4-carbaldehyde (Compound 221), or a tautomer or pharmaceutically acceptable salt thereof.

-   5-(imidazo[1,2-a]pyridin-8-ylmethoxy)-2-methoxyisonicotinaldehyde, -   2-methoxy-5-((5-methylpyridin-3-yl)methoxy)isonicotinaldehyde, -   5-(isoquinolin-1-ylmethoxy)-2-methoxyisonicotinaldehyde, -   2-methoxy-5-(quinolin-2-ylmethoxy)isonicotinaldehyde, -   2-methoxy-5-(pyridin-4-ylmethoxy)isonicotinaldehyde, -   3-(imidazo[1,2-a]pyridin-8-ylmethoxy)-6-methylpicolinaldehyde, -   methyl     2-((4-formyl-6-methoxypyridin-3-yloxy)methyl)imidazo[1,2-a]pyridine-8-carboxylate, -   2-methoxy-5-((3-methoxy-[1,2,4]triazolo[4,3-a]pyridin-8-yl)methoxy)isonicotinaldehyde, -   5-((2-bromopyridin-3-yl)methoxy)-2-methoxyisonicotinaldehyde, -   5-((2-(1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-2-methoxyisonicotinaldehyde, -   5-((5-bromopyridin-3-yl)methoxy)-2-methoxyisonicotinaldehyde, -   2-methoxy-5-((5-(1-methyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)isonicotinaldehyde, -   5-((4-formyl-6-methoxypyridin-3-yloxy)methyl)nicotinic acid, -   2-methoxy-5-(quinolin-3-ylmethoxy)isonicotinaldehyde, -   2-methoxy-5-((1-methyl-1H-indazol-4-yl)methoxy)isonicotinaldehyde, -   tert-butyl     4-((2-formyl-6-methylpyridin-3-yloxy)methyl)-1H-indazole-1-carboxylate, -   6-methyl-3-((1-methyl-1H-indazol-6-yl)methoxy)picolinaldehyde, -   6-methyl-3-((1-methyl-1H-indazol-7-yl)methoxy)picolinaldehyde, -   3-(isoquinolin-1-ylmethoxy)-6-methylpicolinaldehyde, -   5-(benzo[d]oxazol-4-ylmethoxy)-2-methoxyisonicotinaldehyde, -   3-((1,5-naphthyridin-4-yl)methoxy)-6-methylpicolinaldehyde, -   6-methyl-3-((1-methyl-1H-indazol-5-yl)methoxy)picolinaldehyde, -   6-methyl-3-(quinolin-5-ylmethoxy)picolinaldehyde, -   2-methoxy-5-((quinolin-5-ylmethoxy)isonicotinaldehyde, -   2-methoxy-5-((2-(1-methyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)isonicotinaldehyde, -   2-methoxy-5-((2-(1-methyl-1H-pyrazol-3-yl)pyridin-3-yl)methoxy)isonicotinaldehyde, -   5-((2-(2H-tetrazol-5-yl)pyridin-3-yl)methoxy)-2-methoxy)isonicotinaldehyde, -   2-methoxy-5-((2-(4-methyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)isonicotinaldehyde, -   5-((3-(1H-pyrazol-5-yl)isoquinolin-4-yl)methoxy)-2-methoxyisonicotinaldehyde, -   5-((2-(1H-pyrazol-1-yl)pyridin-3-yl)methoxy)-2-methoxyisonicotinaldehyde, -   5-(imidazo[1,5-a]pyridin-8-ylmethoxy)-2-methoxyisonicotinaldehyde, -   5-((2-(1,5-dimethyl-1H-pyrazol-4-yl)pyridin-3-yl)methoxy)-2-methoxyisonicotinaldehyde, -   5-((2-(1-ethyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-2-methoxyisonicotinaldehyde, -   5-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-2-methoxyisonicotinaldehyde, -   2-(difluoromethoxy)-5-(imidazo[1,2-a]pyridin-8-ylmethoxy)isonicotinaldehyde, -   2-methoxy-5-((2-phenylpyridin-3-yl)methoxy)isonicotinaldehyde, -   5-((3-(1-isopropyl-1H-pyrazol-5-yl)pyridin-4-yl)methoxy)-2-methoxyisonicotinaldehyde, -   5-([2,3′-bipyridin]-3-ylmethoxy)-2-methoxyisonicotinaldehyde, -   2-methoxy-5-((2-(o-tolyl)pyridin-3-yl)methoxy)isonicotinaldehyde, -   2-methoxy-5-((2′-methoxy-[2,3′-bipyridin]-3-yl)methoxy)isonicotinaldehyde, -   4-(((2-formyl-6-methylpyridin-3-yl)oxy)methyl)benzoic acid, -   4-(((2-formylpyridin-3-yl)oxy)methyl)benzoic acid, -   methyl 3-(((4-formylpyridin-3-yl)oxy)methyl)benzoate, -   methyl 3-(((2-formyl-6-methylpyridin-3-yl)oxy)methyl)benzoate, -   3-(((4-formylpyridin-3-yl)oxy)methyl)benzoic acid, -   3-(((2-formyl-6-methylpyridin-3-yl)oxy)methyl)benzoic acid, -   3-(((2-formylpyridin-3-yl)oxy)methyl)benzoic acid, -   2-methoxy-5-((2-(1-(2-methoxyethyl)-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)isonicotinaldehyde, -   2-methoxy-5-((2-(1-propyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)isonicotinaldehyde, -   2-methoxy-5-((2-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)methoxyisonicotinaldehyde, -   5-((2-(1-(2,2-difluoroethyl)-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-2-methoxyisonicotinaldehyde, -   3-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin)-3-yl)methoxy)picolinaldehyde, -   3-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-6-methylpicolinaldehyde, -   2-(difluoromethoxy)-5-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)isonicotinaldehyde, -   5-(imidazo[1,2-a]pyridin-8-ylmethoxy)-2-(2-methoxyethoxy)isonicotinaldehyde, -   5-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-2-(2-methoxyethoxy)isonicotinaldehyde, -   5-((3-(1-isopropyl-1H-pyrazol-5-yl)pyridin-2-yl)methoxy)-2-methoxyisonicotinaldehyde, -   3-((4-formyl-6-methoxypyridin-3-yloxy)methyl)picolinate, -   5-((2-(2-hydroxypropan-2-yl)pyridin-3-yl)methoxy)-2-methoxyisonicotinaldehyde, -   2-(2-methoxyethoxy)-5-((2-(1-methyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)isonicotinaldehyde, -   2-(2-methoxyethoxy)-5-((2-(1-methyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)isonicotinaldehyde, -   3-hydroxy-5-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)isonicotinaldehyde, -   3-(benzyloxy)-5-hydroxyisonicotinaldehyde, -   3-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-5-methoxyisonicotinaldehyde, -   5-((2-(2-isopropyl-2H-1,2,4-triazol-3-yl)pyridin-3-yl)methoxy)-2-methoxyisonicotinaldehyde, -   5-((2-(1-isopropyl-4-methyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-2-methoxyisonicotinaldehyde, -   5-((2-(1-(2-hydroxyethyl)-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-2-methoxyisonicotinaldehyde, -   6-(((4-formylpyridin-3-yl)oxy)methyl)picolinic acid, -   2,2,2-trifluoroacetic acid:     6-(((4-formylpyridin-3-yl)oxy)methyl)picolinic acid (1:1), -   2-methoxy-5-((2-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)isonicotinaldehyde, -   5-((2-(4-methyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-2-oxo-1,2-dihydropyridine-4-carbaldehyde, -   5-((2-(1-cyclobutyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-2-methoxyisonicotinaldehyde, -   5-((2-(1-cyclohexylmethyl)-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-2-methoxyisonicotinaldehyde, -   5-((2-(1-(cyclohexylmethyl)-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-2-methoxyisonicotinaldehyde, -   5-((2-(1-cyclopentyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-2-methoxyisonicotinaldehyde, -   2-(5-(3-((4-formyl-6-methoxypyridin-3-yloxy)methyl)pyridin-2-yl)-1H-pyrazol-1-yl)acetic     acid, -   methyl     3-(5-(3-(((4-formyl-6-methoxypyridin-3-yl)oxy)methyl)pyridin-2-yl)-1H-pyrazol-1-yl)propanoate, -   3-(3-(3-(4-formyl-6-methoxypyridin-3-yloxy)methyl)pyridin-2-yl)-1H-pyrazol-1-yl)propanoic     acid, -   3-(5-(3-(((4-formyl-6-methoxypyridin-3-yl)oxy)methyl)pyridin-2-yl)-1H-pyrazol-1-yl)propanoic     acid, -   3-(((4-formyl-6-methoxypyridin-3-yl)oxy)methyl)benzoic acid, -   6-(((4-formylpyridin-3-yl)oxy)methoxy)nicotinonitrile     2,2,2-trifluoroacetate, -   6-(((4-formylpyridin-3-yl)oxy)methyl)nicotinic acid, -   6-(((4-formylpyridin-3-yl)oxy)methyl)nicotinic acid hydrochloride, -   6-(((4-formylpyridin-3-yl)oxy)methyl)-N-(methylsulfonyl)nicotinamide, -   2,2,2-trifluoroacetic acid:     6-(((4-formylpyridin-3-yl)oxy)methyl)-N-(methylsulfonyl)nicotinamide     (2:1),     2-(2-methoxyethoxy)-5-((2-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl)pyridin-3-yl)methoxy)isonicotinaldehyde, -   2-methoxy-5-((2-(1-(3,3,3-trifluoropropyl)-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)isonicotinaldehyde, -   2-(2-methoxyethoxy)-5-((2-(1-(3,3,3-trifluoropropyl)-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)isonicotinaldehyde, -   2-methyl-5-((2-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)isonicotinaldehyde, -   2-methyl-5-((2-(1-(3,3,3-trifluoropropyl)-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)isonicotinaldehyde, -   3-((2-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)isonicotinaldehyde, -   3-((2-(1-(3,3,3-trifluoropropyl)-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)isonicotinaldehyde, -   3-chloro-5-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)isonicotinaldehyde, -   3-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-5-methylisonicotinaldehyde, -   3-chloro-5-((2-(1-(3,3,3-trifluoropropyl)-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)isonicotinaldehyde,     and -   3-methyl-5-((2-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)isonicotinaldehyde, -   or a tautomer or pharmaceutically acceptable salt thereof. 

1.-13. (canceled)
 14. A compound selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.
 15. A compound of selected from the group consisting of:

or an N oxide thereof, or a pharmaceutically acceptable salt of each thereof.
 16. A pharmaceutical composition comprising a compound of claim 14, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.
 17. A method for increasing oxygen affinity of hemoglobin S in a subject, the method comprising administering to a subject in need thereof a compound of claim 14, or a pharmaceutically acceptable salt thereof.
 18. A method for treating sickle cell disease, the method comprising administering to a subject in need thereof a compound of claim 14, or pharmaceutically acceptable salt thereof.
 19. A pharmaceutical composition comprising a compound of claim 15, or an N oxide thereof, or a pharmaceutically acceptable salt of each thereof, and at least one pharmaceutically acceptable excipient.
 20. A method for increasing oxygen affinity of hemoglobin S in a subject, the method comprising administering to a subject in need thereof a compound of claim 15, or an N oxide thereof, or a pharmaceutically acceptable salt of each thereof.
 21. A method for treating sickle cell disease, the method comprising administering to a subject in need thereof a compound of claim 15, or an N oxide thereof, or a pharmaceutically acceptable salt of each thereof. 